Heloderma - University of California Press · chosen for the Gila Monster because E.D. Cope suspected it was venomous (Cope 1869), but it was not until well into the twentieth century

41

he most widely recognized featureof the Helodermatidae family is that its

members are venomous. Misunderstandingand confusion about this trait have accompa-nied Heloderma since before the genus wasdescribed by Hernández in 1577. As discussedin chapter 1, the specific epithet, suspectum, waschosen for the Gila Monster because E.D. Copesuspected it was venomous (Cope 1869), but itwas not until well into the twentieth centurythat scientists agreed that, indeed, this wastrue. Debate continues over whether the venomis used for prey acquisition or defense, and,more recently, promise has arisen over its po-tential applications in modern medicine andpharmacology.

In this chapter, I outline the structure andfunction of the venom delivery system of helo-dermatid lizards. I provide a historical overview,synthesize recent developments in venom bio-chemistry, and consider the function of thevenom system in its ecological context. I con-clude the chapter with an overview of enveno-mation history and the treatment of bites.

HISTORICAL OVERVIEW

Several authors in the latter half of the nine-teenth century commented on the “vile nature”of Heloderma and recognized that its uniquegrooved dentition might be associated with avenomous bite (see Bogert and Martín del

Campo 1956). But it was not until the 1880sthat the anatomy of the venom gland was inves-tigated (Fischer 1882), and experiments wereconducted to show that its salivary secretionswere, in fact, toxic to other animals (Mitchelland Reichert 1883). Instead of resolving uncer-tainty about the venomous nature of Heloderma,however, this work served to initiate a contro-versy that lasted for several decades. Subse-quent experiments (Yarrow 1888) failed to showtoxic effects of Heloderma venom, probably be-cause inappropriate methods were used to col-lect the venom. Additional investigators exam-ined the histology of the venom gland (Holm1897) and showed, with controls, that carefullyextracted venom injected into small vertebrateshad lethal effects (Santesson 1897; Van Den-burgh 1898; Van Denburgh and Wight 1900).Nevertheless, skepticism remained. Snow(1906), having suffered a bite without experi-encing serious pain or swelling, again raisedthe question of whether Heloderma was ven-omous. In 1907, Goodfellow made the follow-ing statement: “. . . exhaustive studies weremade by some of the attaches of the Smithson-ian Institution, among whom was Dr. R.E.Shufeldt, concerning the nature of the animal,and conclusions reached which the writer hadpreviously attained—that the reptile was non-venomous; and it may be accepted as conclu-sively demonstrated that the bite of the “monster”is innocuous per se. In 1913, an authoritative,

CHAPTER 3

The Venom System and Envenomation

T

244-page book summarizing detailed studies ofthe venom of Heloderma was published by theCarnegie Institution of Washington (Loeb et al.1913). This book contained detailed studies by 11contributors on numerous aspects of the venom,including its biochemistry and effects on variousphysiological systems in a number of organ-isms. By the 1920s, this book, and additionalstudies on the venom gland, venom effects, andvenom characteristics by Phisalix (1911, 1912,1917, 1922), finally convinced the scientific com-munity that helodermatid lizards were indeedvenomous, and the debate was settled over the“suspected” venomous nature of Heloderma.

VENOM DELIVERY SYSTEM

Heloderma delivers venom through an efficientsystem consisting of paired venom glands thatempty through ducts at the base of venom-conducting teeth. Venom is produced andhoused in multilobed venom glands (fig. 9),which, unlike those of venomous snakes, are lo-cated in the lower jaw and drain through ductsassociated with each of the lobes. In contrast,the venom glands of snakes are situated behindthe eye, above the upper jaw, and drain througha single duct that leads to an opening at the baseof the associated fang (Greene 1997). Thevenom glands of Heloderma are not surroundedby compressor musculature as in most ven-omous snakes. Instead, tension within theglands produced by jaw movements propels

venom toward the venom-conducting teeth, andcapillary action carries the venom from groovedteeth into the wound.

The structure of the venom gland was firstdescribed by Fischer (1882), but the most com-plete descriptions to date remain the work ofFox (1913) and Phisalix (1912, 1917). More re-cent reviews (e.g., Bogert and Martín del Campo1956; Tinkham 1971b; Russell and Bogert 1981),as well as what I provide below, are largely sum-maries of this earlier work.

The venom glands of helodermatid lizardsare visible externally as conspicuous swellingsbelow the lower lips (fig. 9, plate 20). Eachgland is surrounded by a fibrous capsule fromwhich septa extend to divide the gland intothree or four distinct lobes (fig. 9). Each lobe ofthe venom gland is a structurally independentorgan that forms a sac with a swollen glandularregion at its base and a narrowed excretory ductnear the upper end, which empties at the baseof the teeth in the lower jaw (fig. 10). Each lobeof the venom gland is subdivided (by septa) intoseveral lobules, which are further subdividedinto smaller lobules. These subdivisions con-tinue to occur, resulting in tiny chambers, oralveoli, each separated from one another by adelicate septum. The cavities within the alveoliare continuous with the lobules, which are, inturn, continuous with one another, forming anetwork of intralobular tubules. It is withinthese structures, apparently, that venom is pro-duced by columnar, granule-secreting cells that

42 t h e v e n o m s y s t e m a n d e n v e n o m a t i o n

FIGURE 9. The venom glands of helodermatid lizards are located in the lower jaw. Each gland comprises three or four distinctlobes as shown in these 2 views of a Gila Monster’s right lower mandible with the skin removed (drawings by Randy Babb).

(a) (b)

t h e v e n o m s y s t e m a n d e n v e n o m a t i o n 43

line the intralobular tubules. As these cells dis-charge their contents, the secreted granulesflow from the tubules into a central collectinglumen, which connects to the excretory duct.The lumen, along with associated tubules and

alveoli, apparently also serves as a storage reser-voir for venom.

Helodermatids are not specialized for inject-ing large quantities of venom during brief con-tact, as are many venomous snakes, but thevenom delivery system is structured to quicklyand effectively transfer venom into a bite. Dur-ing biting, tension produced in the gland by jawmovements propels venom through the venomducts into a region between the fourth and sev-enth pair of dentaries (counting from the front),where the teeth show their greatest specializa-tion for piercing and venom delivery. A series ofsmall folds and grooves in the membranous tis-sue within this region serves as a temporaryreservoir for the venom and may facilitate theflow of venom from duct to tooth. When thelizard bites, venom flows from these reservoirsthrough the grooved teeth into the wound.

Each specialized tooth has two grooves, witha shallower (sometimes absent) groove towardthe rear (fig. 11) . Each groove is flanked by a cut-ting flange, which makes the tooth betteradapted for piercing flesh than a merely conicaltooth. Not all the teeth are similar in structureor size. The largest, most deeply grooved teethare the dentaries (in the lower jaw), which canbe up to 6 mm long in H. horridum and 5 mmlong in H. suspectum (fig. 11). The maxillary

FIGURE 10. This cross section through the anterior portionof the right mandible shows relationships of the primarystructures of the venom delivery system of helodermatidlizards. Each lobe of the venom gland forms a sac with anarrowed excretory duct near its upper end. The duct emp-ties at the base of venom-conducting teeth in the lower jaw.

FIGURE 11. Skull of Heloderma suspectum showing arrangement of venom-conducting teeth (top). The largest, most deeplygrooved teeth are the dentaries (in the lower jaw), which can be up to 5 mm long in H. suspectum (drawings by Randy Babb).

VENOM GLAND

JAW BONE

DENTAL CUP

TOOTH

TONGUE

VENOM DUCT

LABIAL GROOVE

EPIDERMIS

teeth (in the upper jaw) are shorter and lessstrongly grooved. Some teeth (especially thepremaxillaries toward the front of the mouth)are hardly grooved at all, but they can still effec-tively deposit venom into an adversary (Tinkham1956; Strimple et al. 1997).

Jaw movements other than those associatedwith biting may also produce sufficient tensionwithin the glands to bathe all the teeth invenom. An agitated lizard will often display adefensive posture of opening its jaws wide (ex-posing the purplish-white interior of its mouth)then closing and reopening the jaws as a threatcontinues. This behavior may serve to bathe themaxillary teeth, dentaries, and premaxillaries invenom preparatory to envenomation.

The quantity of venom deposited into the vic-tim may vary with many factors, including size ofthe lizard, degree of agitation, and length of timeit remains attached. In captive Gila Monsters,quantities ranging from 0.5 to 2.0 ml in a singlemilking have been extracted by a variety of meth-ods (Loeb et al. 1913; Arrington 1930; Brown andLowe 1955; Alagón et al. 1982; fig. 12).

EFFECTS OF THE VENOM

The most complete investigation of the effectsof Heloderma venom remains the work of Loebet al. (1913) who tested hundreds of species, in-cluding invertebrates. Invertebrates are essen-tially immune to the effects of Helodermavenom. Effects on vertebrates are more severeand varied. Ectotherms appear markedly lesssusceptible to the effects of the venom than doendotherms (Cooke and Loeb 1913). Notably,Gila Monsters appear to be immune to the ef-fects of their own venom (Cooke and Loeb 1913;Brown and Lowe 1954).

In mammals, major effects include a rapidreduction in carotid blood flow followed by amarked fall in blood pressure, respiratory ir-regularities, tachycardia and other cardiacanomalies, as well as hypothermia, edema andinternal hemorrhage in the gastrointestinaltract, lungs, eyes, liver, and kidneys (table 4).Common symptoms in dogs and cats include

vomiting accompanied by discharge of urineand feces, and copious flow of saliva and tears.Death from large doses of Heloderma venomhas been attributed primarily to respiratorydisturbances (Cooke and Loeb 1913). Post-mortem examinations reveal congestion andedema in the lungs, a marked congestion ofthe serous layer of the stomach and intestines,and hemorrhage in the kidneys and liver(Cooke and Loeb 1913; Ariano Sánchez 2003).Sublethal doses in mice and rats produce pro-trusion of the eyes and periorbital bleeding(Cooke and Loeb 1913; Ariano Sánchez 2003),and in rabbits they lead to an increase in thenumber of white blood cells (Meyers and Tuttle1913). In humans, the effects of bites are asso-ciated with excruciating pain that may extendwell beyond the area bitten and persist up to24 hours. Other common effects of Helodermabites on humans include local edema (swelling),weakness, sweating, and a rapid fall in bloodpressure (see below). A summary of the effectsof Heloderma venom on mammals is given intable 4.

The lethal dose (LD50) of Heloderma venomvaries among studies and venom lots (Russelland Bogert 1981). Such values are influenced bythe relative amounts of venom and saliva col-lected in each sample and are, therefore, diffi-cult to evaluate. The venom is most toxic whenadministered intravenously in mice, with LD50

values varying from 0.4 to 2.7 mg/kg for H.suspectum (table 5). With an i.v. LD50 of 1.4 to 2.7mg/kg, the venom of H. horridum appears tohave toxicity similar to that of H. suspectum.The LD for H. horridum charlesbogerti venom is1.0 mg/kg when injected intramuscularly inrats (Ariano Sánchez 2003). When injected intomammals, the venom of Heloderma appears to be about as toxic as that of the WesternDiamondback Rattlesnake, Crotalus atrox (Russelland Bogert 1981).

CHEMICAL MAKEUP OF THE VENOM

As knowledge of the toxic effects produced byHeloderma venom increased, so did interest in



the chemical constituents causing these symp-toms. The first studies on the chemical natureof Heloderma venom (Santesson 1897) identi-fied two “toxic principles,” referred to as nu-clein and albuminose, but it was not until 1913that the first toxin, a lipase, was isolated (Als-berg 1913). The 1960s saw renewed interest inthe chemistry of Heloderma venom. Serotoninand amine oxidase activity were identified in

the venom of H. horridum in 1960 (Zara-fonetis and Kalas 1960). Mebs and Raudonat(1966) identified a very active hyaluronidase (aspreading factor; see below), phospholipase A,and a kinin-releasing enzyme with small pro-teolytic activity in both H. horridum and H. sus-pectum venom. In 1967, Tu and Murdochshowed that H. suspectum venom was largely amixture of proteins, some of which hydrolyze

TABLE 4Effects of Venom of Helodermatid Lizards in Nonhuman Mammals

effects references

RespirationInitial increase in rate, “forced” respirations Cooke and Loeb 1913

followed by decrease and eventual standstillVentilatory irregularities: gasping, rapid, shallow Patterson 1967a

breaths, apnea

Cardiovascular SystemMarked and rapid fall in blood pressure Mitchell and Reichert 1883Initial tachycardia Van Denburgh and Wight 1900Cardiac irregularities Fleisher 1913Impaired cardiac function/cardiac failure Patterson 1967aReduction in carotid blood flow and arterial Russell and Bogert 1981

blood oxygenationCyanosis

HemorrhageGI tract Cooke and Loeb 1913Intestines, kidneys, lungs Patterson 1967aEyes Styblová and Kornalik 1967Liver Ariano Sánchez 2003

BloodLeucocytosis Meyers and Tuttle 1913No effect on blood coagulation time Cooke and Loeb 1913Prolonged prothrombin time (anticoagulation) Patterson and Lee 1969

Smooth MuscleStimulating effect in ileum, colon, uterus Patterson 1967b

Edema (note also with human envenomation)Intestines, stomach, lungs Cooke and Loeb 1913

Other EffectsParalysis of limbs, partial paralysis of body Patterson 1967aProtrusion of eyes (exophthalmia) Cooke and Loeb 1913LacrimationAbdominal rigidityConvulsionsVomiting

NOTE: Based on in vivo studies in cats, dogs, guinea pigs, mice, and rats.

certain peptides. Patterson and Lee (1969)later showed coagulation was affected ifvenom was incubated with blood plasma forlonger periods. Subsequent work isolated he-morrhagic toxins in the venom (Nikai et al.1988; see below). In the late 1960s, Mebs iso-lated kallikrein from the venom of H. suspec-tum (Mebs 1968, 1969). Murphy et al. (1976)demonstrated enzyme activities in the venomof H. horridum. In the 1980s, additional pro-teins—gilatoxin (Hendon and Tu 1981), hor-ridum toxin (an arginine ester hydrolase;Alagón et al. 1982; Nikai et al. 1988), heloder-matine (a kallikrein-like hypotensive enzyme;Alagón et al. 1986), an additional phospholi-pase (A2; Gomez et al. 1989), and helother-mine (Mochca-Morales et al. 1990)—were dis-covered and added to the known arsenal ofHeloderma venom components.

With the discovery in the 1980s that Helo-derma venom contained strongly bioactiveagents, with hormonelike actions similar to va-soactive intestinal peptides (VIP), interest andresearch in these intriguing molecules acceler-ated dramatically (Raufman 1996). Five bioac-tive peptides have been isolated so far from the

venoms of Gila Monsters and Beaded Lizards:helospectin I and II (Parker et al. 1984), helo-dermin (Hoshino et al. 1984), exendin-3 (foundin H. horridum; Eng et al. 1990), and exendin-4(found in H. suspectum; Eng et al. 1992). Thesepeptides mimic several human neurosecretoryhormones that relax smooth muscle and medi-ate energy metabolism. The major compoundsso far identified in the venom of helodermatidlizards as well as their chemical nature andphysiological effects are discussed below andsummarized in table 6.

HYALURONIDASE

Hyaluronidase is a hydrolase enzyme thatcleaves internal glycosidic bonds of hyaluronicacid, a mucopolysaccharide that is an importantcomponent of connective tissue. Because thisaction facilitates venom diffusion into the tissue(Tu and Hendon 1983), hyaluronidase has beentermed spreading factor. Hyaluronidase is alsocommon in snake venoms where it also acts asa spreading factor (Meier and Stocker 1995).Venom of both Heloderma species shows partic-ularly high hyaluronidase activity, which is be-lieved to explain the potent edema effects of


TABLE 5 LD50 of Heloderma Venom in Mice and Rats

avenue species ld50 (mg/kg) species

Johnson et al. 1966 Intraperitoneal mice 3.0 suspectumMebs and Raudonat 1966 Subcutaneous mice 0.82 suspectumStahnke 1966 Intraperitoneal rats 10.3 suspectumStahnke 1966 Intraperitoneal mice 3.0 suspectumPatterson 1967a Intracardiac rats 1.35 suspectumStyblová and Kornalik 1967 Intravenous mice 0.4 suspectumStyblová and Kornalik 1967 Subcutaneous mice 4.0 suspectumTu and Murdock 1967 Subcutaneous mice 2.0 suspectumStahnke et al. 1970 Subcutaneous rats 14.0–16.8 suspectumHendon and Tu 1981 Intravenous mice 2.7 suspectumRussell and Bogert 1981 Intravenous mice 0.52 suspectumMebs and Raudonat 1966 Subcutaneous mice 1.4 horridumHendon and Tu 1981 Intravenous mice 2.7 horridumAlagón et al. 1982 Intraperitoneal mice 2.0 horridumAriano-Sánchez 2003 Subcutaneous rats 1.0 horridum

charlesbogerti

TABLE 6 Major Constituents of Heloderma Venom and Their Actions

description/action physiological effects

Hyaluronidase Hydrolase enzyme; cleaves hyaluronic acid Acts as a “spreading factor” by facilitating diffusion of venom through connective tissues surrounding bite site

Serotonin Neurotransmitter hormone Mediates inflammation, vasodilation, smooth muscle activity, andother effects

Phospholipase A2 Hydrolase enzyme; catalyze hydrolysis Presynaptic membrane toxins in snakes; effects of Helodermaof phospholipid glycerol backbone phospholipase A2s are unknown

Nerve Growth Factor Induce nerve growth; degranulate mast cells Effects unknownHelothermine 25-kDa peptide with similarity to family of Causes lethargy, partial paralysis of rear limbs, intestinal distension,

mammalian cysteine-rich secretory proteins and hypothermia in ratsGilatoxin 33-kDa serine protease glycoprotein Kallikrein-like lethal toxin; causes lowered blood pressure and

contraction of isolated uterus smooth muscle in ratsHorridum toxin 31-kDa glycoprotein similar to gilatoxin Kallikrein-like lethal toxin; causes hypotension, hemorrhage in

internal organs, hemorrhage and bulging of the eyesHelodermatine 63-kDa serine protease glycoprotein Kallikrein-like enzyme; causes a dose-dependent decrease in arterial

blood pressure in ratsUnnamed lethal toxin 28-kDa peptide Kallikrein-like lethal toxin that suppresses contraction of isolated

diaphragm muscle in miceHelospectin I & II 37- to 38-amino-acid peptides from exocrine Stimulate amylase release from the pancreas; show physiological

(exendin-1) gland having endocrine function effects similar to VIP (vasoactive intestinal peptide); have been localized in various human tissues

Helodermin (exendin-2) Basic 35-amino-acid peptide with stable Causes hypotension in dogs and rats; shows physiological effectssecondary structure similar to VIP

Exendin-3 39-amino-acid (4.2-kDa) peptide from Interacts with newly described exendin receptor and mammalian VIPH. horridum venom receptors; induces amylase release from the pancreas

Exendin-4 (exenatide) 39-amino-acid peptide from H. suspectum venom Induces insulin release through activation of glucagon-like peptide-1 (GLP-1) receptor

Gilatide Fragment of exendin-4 peptide Acts on GLP-1 receptor; improves memory in rodents

NOTE: See text for more complete descriptions and references.

Heloderma bites (Mebs and Raudonat 1966;Russell and Bogert 1981).

SEROTONIN

Serotonin, derived from the amino acid trypto-phan, produces potent local physiological ef-fects and also functions as a neurotransmitter.Serotonin mediates local processes such as in-flammation, vasodilation, and smooth muscleactivity and causes aggregation of platelets(Greger 1996). It is found in a variety of toxinsfrom animals such as spiders, toads, and wasps.The specific in vivo effects from the serotoninfound in Heloderma venom are not known, al-though it likely participates in the inflammationresponse.

PHOSPHOLIPASE A2

Phospholipase A2 enzymes are classified as hy-drolases that act on ester bonds in fat molecules(phospholipids). These common constituentsof viperid and elapid snake venoms are toxic topresynaptic membranes, disrupting the releaseof neurotransmitters at nerve synapses and neu-romuscular junctions and inhibiting platelets(among other actions; Rosenberg 1988; Meierand Stocker 1995). This behavior can causeparalysis and loss of muscle control and func-tion, among other signs. We do not knowwhether phospholipase A2 from Heloderma isresponsible for such actions in humans andother mammals because the specific in vivo ef-fects of this enzyme have not been investigated.However, phospholipase A2 enzymes from H.horridum have been shown to inhibit plateletaggregation in human blood plasma (Huangand Chiang 1994).

Five variants of phospholipase A2 (or PLA2)have been identified and characterized in thevenom of H. suspectum (Sosa et al. 1986;Gomez et al. 1989; Vandermeers et al. 1991).All of these stimulate the release of amylasefrom secretory cells (acini) in rat pancreatic tis-sue, and they hydrolyze phosphatidylcholines(lecithins), which are important in cell structureand metabolism. Gila Monster PLA2s are appar-ently quite different from those found in snake

venoms, especially in their N-terminal aminoacid sequences and molecular weight (Tu 1991;Vandermeers et al. 1991). Interestingly, they aremost similar to PLA2 from bee venom. The majorvariant of PLA2 in Gila Monsters (Pa5) shows a C-terminal extension seen only in Heloderma andbee (Apis mellifera) venoms (Gomez et al. 1989).

NERVE GROWTH FACTOR

Nerve growth factors are found in a number ofviperid and elapid snake venoms. They nor-mally induce the growth of nerve tissues, butthey may also contribute to the toxic action ofvenoms by degranulating mast cells, which con-tributes to inflammation (Meier and Stocker1995). A nerve growth factor was discovered inthe venom of H. horridum in 1968 (Levi-Montalcini and Angeletti 1968), but its role re-mains unexplored.

HELOTHERMINE

This toxin from H. horridum venom is a 25.5kDa protein with an N-terminal amino acid se-quence initially thought to be unique (Mochca-Morales et al. 1990). Further characterization ofhelothermine showed it to have structural ho-mology with a family of cysteine-rich secretoryproteins found in mammalian male genitaltracts and in salivary glands, as well as in someother animal toxins (Morrissette et al. 1995; R. L. Brown et al. 1999). When injected intomice, helothermine causes lethargy, partialparalysis of rear limbs, intestinal distension,and lowering of body temperature; hence, as itsname suggests, it is a potentially hypothermictoxin (Mochca-Morales et al. 1990). Althoughdeadly to mice, its LD50 has not been reported(Mochca-Morales et al. 1990). Helothermineblocks certain ion channels in cell membranes(e.g., calcium channels in cardiac muscle, skele-tal muscle, and cerebellar granules; Morrissetteet al. 1995; Nobile et al. 1994, 1996). This prop-erty gives it promise as a pharmacological toolfor studies on the structure and function of ionchannels in muscle and brain tissue. Unlikeother toxins found in the venoms of heloder-matid lizards (discussed below), helothermine


shows no enzymatic effects. Helothermine is amember of the helveprins (20–25 kDa pro-teins), which are found in many reptile venoms(S.P. Mackessy, pers. comm.).

THE KALLIKREIN-LIKE TOXINS

These are the toxins most responsible for theexcruciating pain that results from the bites ofGila Monsters and Beaded Lizards. Four differ-ent proteins that possess kallikrein-like toxinshave been identified in the venom of heloder-matid lizards (table 6). Kallikreins are hy-potensive hormones that exert powerful localphysiological effects. They cleave kinogensthat, in turn, release bradykinins—local hor-mones that mediate the inflammation/painresponse. Bradykinins produce pain by stimu-lating both sensory C-fibers and spinal ganglia,and they reduce blood sugar by shifting D-glu-cose from plasma to muscle (Greger 1996).Bradykinins also cause vasodilation of periph-eral arterioles and increased vascular perme-ability, which results in edema (swellingcaused by leaking of plasma fluid into tissues).Bradykinins also stimulate secretion of adren-aline, which can cause an increase in heartrate, among other effects. Plasma concentra-tions of bradykinins are usually very low(4 pmol/L) so local increases in these sub-stances can have dramatic effects (Greger1996). Kallikreins in venoms of viperids maycontribute to the immobilization of prey ani-mals (Meier and Stocker 1995).

As with helothermine, above, the first threekallikrein-like proteins have been shown to belethal toxins.

GILATOXIN

Gilatoxin, a glycoprotein, was the first lethaltoxin isolated from the venom of helodermatidlizards (Hendon and Tu 1981). Later researchfound that gilatoxin is one of several toxins inHeloderma venom that shows kallikrein-like ac-tivity (Utaisincharoen et al. 1993). Present inboth species, it comprises about 3%–5% of thevenom volume. Gilatoxin is a serine proteasethat acts on a number of substrates including

kininogen and angiotensin, which are involvedin mediating blood pressure. Gilatoxin appearsto be found only in helodermatid lizards andhas an LD50 of 2.6–2.9 �g/g. Interestingly, itbecomes more toxic when administered to micein combination with other venom fractions(Tu 1991), suggesting that the toxin acts synergis-tically with additional venom components.

HORRIDUM TOXIN

Horridum toxin, from the venom of H. hor-ridum, is the only hemorrhagic toxin so farisolated from helodermatid lizards. Anotherglycoprotein, horridum toxin is a distinct formof gilatoxin, but with a similar structure (Nikaiet al. 1988; Datta and Tu 1997; Tu 2000). Italso shows kallikrein-like activity, releasingbradykinin upon hydrolysis of kinogen (Dattaand Tu 1997). Similar to gilatoxin, it hasstrong hypotensive effects when injected intorats. It is more toxic than gilatoxin, showingan LD50 of 0.38 �g/g (Nikai et al. 1988). In ad-dition to the inflammatory effects produced bybradykinin, horridum toxin causes hemor-rhage in internal organs and especially in theeye, leading to exophthalmia (protrusion ofthe eyeballs), an effect that has not been ob-served from other venoms (Datta and Tu1997). The actual exophthalmic effect, how-ever, occurs only when the kallikrein activity iscontaminated with a similar-sized metallopro-tease (S.P. Mackessy, pers. comm.). Althoughhorridum toxin has been isolated only fromH. horridum, exophthalmia has also been ob-served in rats and mice injected with venomfrom H. suspectum (Cooke and Loeb 1913; Pat-terson 1967a; Styblová and Kornalik 1967),suggesting a similar toxin may also be presentin the venom of the Gila Monster. Horridumtoxin has been shown to degrade fibrinogen tofibrin, an important step in the blood coagula-tion process that is normally performed by theenzyme thrombin. Clots do not form fromhorridum toxin poisoning, however, suggest-ing that it does not act like thrombin, as domany snake venoms that show kallikrein-likeactivity.


UNNAMED LETHAL TOXIN

Another very toxic “lethal toxin” was isolatedfrom the venom of H. horridum by Komori et al.(1988). This toxin has a molecular weight of 28kDa and an LD50 of 0.135 �g/g when injected in-travenously in mice. This appears to be themost toxic substance isolated so far from thevenom of Heloderma. The toxin suppresses con-traction of the diaphragm muscle in mice, butshows no hemolytic or hemorrhagic activity.Proteolytic, phospholipase A2, or arginine esterenzymatic activity are all absent in this appar-ently novel toxin (Kamori et al. 1988).

HELODERMATINE

Not considered a lethal factor, helodermatine isan arginine esterase purified from H. horridumvenom. It was the first enzyme with kallikrein-like activity to be isolated and characterizedfrom Heloderma venom (Alagón et al. 1986).Helodermatine is another serine protease glyco-protein, as are gilatoxin and horridum toxin,but, at 66 kDa, it is about twice their molecularmass. When injected into anesthetized rabbits,it causes a rapid dose-dependent decrease in ar-terial blood pressure, an effect likely attributedto its active kallikrein nature. Its N-terminalamino acid sequence is similar to kallikreinfrom pig pancreas and to kallikrein-like en-zymes from venom of the rattlesnakes Crotalusatrox and C. adamanteus.

THE BIOACTIVE PEPTIDES

In the early 1980s, investigators searching forbiologically active chemicals in animal venomsmade a very important discovery. They foundthat the venom of helodermatid lizards eliciteda spectacular secretory response from pancre-atic acini (secretory cells that make a usefulmodel system for testing the biological activityof chemical substances; Raufman 1996). Thisdiscovery led to an intense effort to find thecompounds responsible for this response,which culminated in 1984 with the descriptionof helospectin I and II (Parker et al. 1984) andhelodermin (Hoshino et al. 1984). These pep-tides are similar in structure and action to VIP

(vasoactive intestinal peptide), a hormone se-creted by nerves found throughout the gastroin-testinal tract. A neurotransmitter hormone, va-soactive intestinal peptide is a powerful relaxantof smooth muscle (hence its name) and medi-ates the secretion of water and electrolytes bythe small and large intestines. (Interestingly,VIP-secreting tumors give rise to “pancreaticcholera” with symptoms similar to those shownby a severe bite case—see below.) The actionsand structure of VIP are also similar to secretin,another messenger peptide involved in stimu-lating pancreatic secretions. In the early 1990s,two additional biologically active peptides, ex-endin-3 and exendin-4, were discovered in thevenom of helodermatid lizards (Eng et al. 1990,1992). Exendins are so named because they arepeptides from exocrine glands (of Heloderma)having endocrine actions (Eng et al. 1990). Thehelospectins became known as exendin-1 andhelodermin as exendin-2.

Exendins (including helospectins and helo-dermin) exert their biological effects by interact-ing with specific receptors found on cell mem-branes in various tissues of mammals. Thereceptors known to be involved include VIP andsecretin receptors, exendin receptors (newlydiscovered because of work with Helodermavenom), and GLP-1 receptors (involved in in-sulin release and glucose metabolism). The ef-fects of these bioactive peptides are numerousand diverse, but they generally involve decreaseof blood flow via effects on smooth muscle, andactivation of adenyl cyclase. Adenyl cyclase, anenzyme released when a mammal requiresenergy, catalyzes a reaction that results in theformation of cAMP, which, in turn, activatesnumerous enzymes including those that me-tabolize carbohydrates for energy production.An excellent review of bioactive peptides fromHeloderma is given in Raufman (1996). The na-ture and action of these interesting peptides arediscussed below.

THE HELOSPECTINS

Helospectin I and II are very similar peptides(38 and 37 amino acids, respectively) that


stimulate amylase release from the pancreas.Helospectin I differs from helospectin II in thatit has an additional serine residue at its C ter-minus. It is believed that, because of theirsimilar actions, helospectins and VIP act on acommon membrane receptor in mammals(Grundemar and Hogestatt 1990). Six forms ofhelospectin have recently been identified fromH. horridum venom that show minor differ-ences in the side groups attached to their Ser32residues (Vandermeers-Piret et al. 2000). Inter-estingly, helospectins (and helodermin) havebeen immunohistochemically localized, usuallyassociated with nerve endings, in a variety ofhuman tissues ranging from the upper respira-tory tract to the genitalia (Graf et al. 1995;Hauser-Kronberger et al. 1996, 1999). In thesetissues, they appear in association with VIP re-ceptors and (as with VIP and secretin) may playa role in regulating secretory activities and localblood flow. The location of these lizard venompeptide sequences within the tissues of mam-mals leads to some intriguing ecological and evo-lutionary questions (see below). The helospectinsare present in venoms of both H. horridum andH. suspectum, but they are more abundant in H. horridum venom.

HELODERMIN

Helodermin, a basic 35-amino-acid peptide dis-covered in Gila Monster venom, was the first se-cretin/VIP-related peptide found in an animalother than a mammal or bird (Hoshino et al.1984; Vandermeers et al. 1984). In dogs, itcauses prolonged, systemic hypotension (Rob-berecht et al. 1988); in rats, it produces a dose-dependent hypotension, apparently via K�

channels that exist on arterial smooth musclecells (Horikawa et al. 1998). The discovery ofhelodermin also included the discovery of an-other bioactive peptide, pancreatic secretory fac-tor, that later turned out to be a member of thephospholipase A2 family (Dehaye et al. 1984;Vandermeers et al. 1984). In comparison withother members of the secretin/VIP family ofpeptides, helodermin has an unusually stablesecondary structure, partly owing to a secondary

configuration it maintains in water, which mayaccount for its prolonged physiological action(Blankenfeldt et al. 1996). Helodermin shows85% identity with helospectin I and II, whichprobably explains the similarity in their biologi-cal activity (Raufman 1996) and also suggests acommon evolutionary origin for these venompeptides. Helodermin binds to receptors in anumber of human tissues in the gastrointesti-nal tract, lungs, and even on human breast can-cer cells (Raufman 1996). It has also beenshown to inhibit growth and multiplication oflung cancer cells (Maruno and Said 1993).Helodermin may also inhibit the activity ofphospholipase A2, suggesting that it could servea protective function to attenuate phospholipaseactivation within the venom glands (Raufman1996). Helodermin is found only in the venomof H. suspectum.

EXENDIN-3 AND EXENDIN-4

The most important peptides in Helodermavenom, in terms of pharmacological applica-tions, are exendin-3 and exendin-4. Exendin-3, a39-amino-acid peptide, occurs in the venom ofH. horridum. It shows similarity with other hor-mones involved in digestion: glucagon (48%)and human glucagon-like peptide-1 (GLP-1;50%). In its 12 amino acid residues, it has stronghomology with secretin (91%), but only 41%with secretin overall, and only 29% similarity toVIP. It shows limited structural similarity withhelospectin and helodermin (32% and 26%, re-spectively; Eng et al. 1990).

Exendin-4, found only in Gila Monstervenom, differs from exendin-3 by two aminoacids, suggesting minor evolutionary changesfrom an ancestral peptide (Raufman 1996). Ex-endin-4 shows great structural homology (53%)to human glucagon-like peptide-1, a hormonereleased from the gut in response to a meal(Goke et al. 1993; Raufman 1996; Drucker2001). GLP-1 stimulates insulin release andmoderates blood glucose levels, traits that haveattracted interest in its potential for treatingType II (noninsulin dependent) diabetes (Gokeet al. 1993; Doyle and Egan 2001). In the blood,


GLP-1 has a short half-life and must, therefore,be administered frequently to maintain ade-quate insulin levels. Exendin-4, on the otherhand, activates the same receptor as GLP-1 butturns out to be more effective at inducing in-sulin release. Moreover, exendin-4 has a muchlonger biological action than GLP-1 (Young et al.1999a; Doyle and Egan 2001). Amylin Pharma-ceuticals, Inc., has developed a synthetic ex-endin-4 (AC 2993) that lowers plasma glucoseto within the normal range, without inducinghypoglycemia, in people with Type II diabetes(Kolterman et al. 1999, 2003). In healthy volun-teers, exendin-4 also reduces plasma glucose bydelaying gastric emptying and by reducing calo-rie intake (Edwards et al. 2001).

These traits have propelled exendin-4 to theforefront of pharmacological research on thetreatment of diabetes. A search of the medical

literature for exendins will turn up hundreds ofpapers published since their discovery in 1990.Adult-onset (Type II) diabetes accounts for mostof the 17 million cases of diabetes in the UnitedStates. Prospects for exendin-4, or its tradename exenatide (AC 2993), currently in phase 3development for use in treating human dia-betes, are so bright that Eli Lilly & Companyclosed a $325 million deal in September 2002with Amylin Pharmaceuticals for rights to de-velop and market a synthetic version of thiscompound (fig. 12).

GILATIDE

This novel nine-amino-acid peptide, discov-ered in 2001, is really a fragment of the largerexendin-4 molecule (Haile et al. 2001, 2002).The extent to which it occurs independently inthe venom of helodermatid lizards is not yet


FIGURE 12. The venom of helodermatid lizards also contains several bioactive peptides that have brought the shy, venomouslizards into pharmacology journals and headlines in medicine. The best-known lizard peptide, exendin-4, mediates insulinrelease and glucose uptake from the blood after a meal. A synthetic version of exendin-4 (exenatide) is a leading candidatefor treating adult-onset (Type II) diabetes, which accounts for most of the 17 million cases of diabetes in the United States.Prospects for this drug are so bright that Eli Lilly & Company recently closed a $325 million deal with Amylin Pharmaceuti-cals for rights to develop and market this compound (photo by Tom Wiewandt).

known. Gilatide has been shown to stronglyenhance memory in mice, based on standardcognition tests. This effect appears to be medi-ated through GLP-1 receptors, a pathway previ-ously unknown to be involved in learning andmemory (Haile et al. 2002). Anonyx, a NewYork–based pharmaceutical company, is in-vestigating the potential for using gilatide tohelp people suffering from memory disorderssuch as those associated with Alzheimer’s dis-ease and attention deficit/hyperactivity disorder(ADHD). Should gilatide indeed turn out to bean active, independent component of heloder-matid lizard venom, what could be a more effec-tive formula for a defensive venom than to mixcomponents producing great pain with one thatalso enhances one’s memory of the experience?

A summary of the major constituents ofHeloderma venom is provided in table 6.Many of these peptides have valuable researchand pharmacological applications. Venom con-stituents have enabled discovery of new mem-brane receptors in mammals, have enlightenedphysiologists as to how these receptors func-tion, and hold promise for treating diseasessuch as cancer and diabetes. The venom of helo-dermatid lizards may be unique among reptilevenoms in showing such a high number ofbioactive peptides (Bertanccini 1976; Raufman1996). Why do several venom constituentsclosely resemble human neurosecretory hor-mones? Why does the venom exhibit a redun-dancy of peptides producing strong kallikrein-like activity? What is the ecological function ofthis complex slurry of peptides, and how do thevarious venom components act to achieve theirecological role, if any? The answers to thesequestions are best considered in an ecologicaland evolutionary context.

ECOLOGICAL/EVOLUTIONARY ROLE OF HELODERMATID VENOMS

Although the biochemistry of Heloderma venomshows great promise in pharmacology, its eco-logical role has received less attention. A peren-nial source of confusion has been whether the

venom system of Heloderma is used primarilyfor defense, or to subdue and aid in digestingprey, as is the case for most venomous snakes.In snakes, venom serves an important feedingrole, primarily in subduing or immobilizingprey that are large, dangerous, or otherwise dif-ficult to handle (Greene 1997). Most vipers im-mobilize their prey by rapidly injecting largequantities of toxins that induce hypotension,clotting, and the enzymatic breakdown of tis-sues, especially the lining of blood vessels(Meier and Stocker 1995; Greene 1997). Manyelapid snakes (e.g., cobras and mambas) injectsmaller quantities of neurotoxins that immobi-lize prey by blocking impulses at the neuro-muscular junction, paralyzing muscles of respi-ration and leading to respiratory failure (Greene1997). Many snake venoms have both tissue-destructive and neurotoxic properties. A sec-ondary feeding role of snake venoms may be toaid in digesting prey, although few studies havedirectly demonstrated this effect (Thomas andPough 1979). Predigestion may be particularlyimportant for viperids that inhabit cooler tem-perate latitudes and feed on relatively large prey(Thomas and Pough 1979; Mackessy 1988;Greene 1997). In contrast to most venomoussnakes, effects of envenomation by Helodermatend to be more localized and, as summarizedabove, show relatively little tissue destruction.

Thus the utility of snake venoms for de-fense, although often profound, is secondary totheir feeding role (Greene 1997). For heloder-matid lizards, on the other hand, an elaboratevenom system seems unnecessary for subduingprey. Beaded Lizards and Gila Monsters are spe-cialized nest predators that feed almost entirelyon eggs or juvenile birds and mammals (seechap. 7). Venom is not needed to subdue de-fenseless young or eggs in vertebrate nests.Helodermatid lizards do not feed on rapidlymoving prey, and, although meals may be large,individual prey tend to be smaller than 10% oftheir adult body mass. The venom system ofHeloderma precludes rapid injecting of venomduring brief contact, a trait that is important forsubduing large prey that are dangerous and


difficult to handle. Moreover, the venom ofhelodermatid lizards does not appear to havesufficient tissue-destroying properties to be ef-fective in helping to predigest prey (see above).

Nor do limited field observations suggest theuse of venom to subdue prey. Wild Gila Mon-sters feeding on juvenile cottontails (relativelylarge prey at approximately 45 g each) delicatelyswallow the nestlings without the characteristicchewing or pumping motions shown when en-venomating an adversary (Beck 1990; chap. 7).In captivity, however, I have observed Gila Mon-sters and Beaded Lizards that were feeding ondead mice “chewing” their prey before swallow-ing them. Although these observations do notrule out a feeding function, they suggest thatthe venom of helodermatid lizards does notserve a major role in subduing prey. In somecases, however, especially for juveniles, it couldaid in immobilizing prey.

A digestive role of the venom might be ruledout entirely were it not for exendin-4, whichcomprises up to 5% of the dry weight of GilaMonster venom (J. Eng, pers. comm.) and hasbeen shown to increase 30-fold in the blood ofGila Monsters immediately after a meal (Younget al. 1999b). This result leaves open the in-triguing possibility that exendin-4 could regu-late glucose uptake in the gut of helodermatidlizards. Could the venom glands, which aremodified salivary glands, serve as a source ofhormones exerting endocrine control of carbo-hydrate metabolism in Gila Monsters andBeaded Lizards? We do not yet know what phys-iological role, if any, exendin serves in Heloderma.It remains to be discovered, or discounted,whether exendin might aid in lizard digestionjust as it may help humans cope with diabetes.So, whereas it seems obvious that helodermatidlizards need not use venom to subdue theirprey, a role of the venom system in processingprey remains a possibility that needs to be fur-ther explored (chap. 10).

For defense, on the other hand, the venomsystem is crucial. Gila Monsters and MexicanBeaded Lizards spend the vast majority of theirtime hidden in shelters, yet they occasionally

travel considerable distances during infrequentaboveground forays (Beck 1990; Beck and Lowe1991). These large, slow-moving lizards cannotquickly sprint away from a potential threat, ascan most other lizards. Their peak speed of 1.7km/hour on a treadmill (Beck et al. 1995) con-trasts strikingly with some inguanine lizards ofsimilar size, which can attain speeds of over 25km/hour (Garland 1984). These traits makesurface-active Heloderma particularly vulnerableto predators. Predation is obviously an impor-tant factor, and Heloderma occasionally suc-cumb to predators (see chap. 6).

Gila Monsters and Beaded Lizards generallyavoid encounters with predators by relying ontheir secretive habits and cryptic patterns.While radiotracking surface-active BeadedLizards in Jalisco, I often observed that, whenlizards noticed my presence from a distance,they would stop moving and press their body tothe ground. As I approached more closely,Beaded Lizards (and Gila Monsters) attemptedto escape but could be easily overtaken andcaptured if they could not quickly flee into aburrow. Thus, when confronted with an adver-sary during an aboveground foray, the inabilityof Heloderma to swiftly escape necessitates aneffective defense.

How effective is the bite of Heloderma at re-pelling potential predators? As an adversary isseized by the jaws of a heloderm, a complexmixture of venom proteins and peptides alsoseizes physiological control of the intruder.Kallikrein-releasing toxins cause immediatebradykinin release accompanied by severe pain,inflammation, weakness, and a rapid drop inblood pressure. Hyaluronidase enzymes facili-tate the spread of venom components throughconnective tissues surrounding the bite site.Horridum toxin may begin causing internalhemorrhaging; helothermine may begin actingto lower body temperature and induce lethargy.

Meanwhile, the heloderm holds on withbulldog tenacity and continues to chew addi-tional venom into the wound. At this point, allof an intruder’s attention must be focused onremoving the venomous lizard from the bitten


area. And herein lies another of the paradoxesof helodermatid lizards. The same behaviorthat so effectively delivers venom to its ene-mies (and makes them wish they had avoidedcontact to begin with) puts the lizard at risk ofinjury as an adversary attempts to remedy itspainful situation.

How can this apparent paradox be resolved?Is the effectiveness of Heloderma’s venomousbite really undermined by its tenacious behav-ior? There are very few recorded accounts of di-rect encounters between Heloderma and theirnatural predators (Sullivan et al. 2002; chap. 6).Of 12 cases of Gila Monster bites on dogs re-ported in Tucson, Arizona, during 2001–02,two resulted in death of the Gila Monster (un-published records, Arizona Poison Control Cen-ter). In most cases, each dog shook off the GilaMonster without seriously injuring it. From re-viewing numerous case histories of Helodermabites on humans (see below), I found only oneinstance in which the lizard was seriously in-jured while being extracted. In most cases, thelizard was forcefully pulled or pried off, and afew teeth broken, while attention was focusedon the bite injury (and not on the lizard). It isplausible that, when bitten by a Heloderma,many natural predators would likewise extractthe lizard without killing it. Occasionally, Helo-derma may also be killed while being removedfrom an adversary. However, it seems unlikelythat, if it survived being bitten, an adversarywould eat the Heloderma (some of the bioactivepeptides present in the venom may even sup-press appetite; Szayna et al. 2000; Edwards etal. 2001). It is equally unlikely that an adversarywould risk future encounters after a bite fromone of these dangerous lizards (a fragment ofthe exendin peptide even helps improve memory;Haile et al. 2002). A predator, therefore, gainsnothing by attacking a Heloderma, but it does riskinjury, incapacitation, or death. Regardless ofwhether the Heloderma were killed, individualsbitten by Gila Monsters or Beaded Lizards wouldvery likely show lower survivorship and reducedreproductive success. Over evolutionary time,predators learn to recognize and avoid noxious

and potentially dangerous prey (S.M. Smith1977; Lindstrom 2001). To the Heloderma, as longas the risk of death does not exceed the benefitsreceived from reduced predation owing to recog-nition by predators, its defensive strategy wouldbe successful. Because this genus has survivedfor at least 23 million years, it appears such astrategy has, indeed, been effective.

Whether or not the venom system seems ef-ficient to us, Heloderma appears to have used iteffectively for a long time. Natural selection doesnot produce adaptations that are perfect by anymeans, and half-baked solutions are often allthat is possible given evolutionary constraints(Gould 1980). Natural selection is limited by theraw material it has to work with, in this case themorphological constraints imposed by the lizardbody plan. Helodermatid lizards do not have ag-ile, elongate bodies that enable them to coil andrapidly strike at a foe (that adaptive zone is thedomain of the snakes), so a highly specializedvenom apparatus designed for efficient injectionof venom through hollow fangs does not makesense for Heloderma, given the niche it fills andthe evolutionary constraints imposed by its gen-eralized lizard morphology.

Lizards (including Heloderma) bite as a finalmeans of defense, and when they do they tendto hang on. Interestingly, Alligator lizards of thegenus Elgaria (family Anguidae, sister group tothe Helodermatidae) bite in a manner similar tohelodermatid lizards. Southern Alligator lizards(Elgaria multicarinata) readily bite when han-dled, hang on tenaciously when biting, and ex-ert greater bite pressure (similar to the chewingactions shown by Heloderma) as attempts aremade to extract them from a bitten extremity(personal observation). For a bite to be effective,a lizard may have no choice but to hang on. Ifthe lizard releases its hold before an adversaryhas been effectively stunned, surprised, or im-mobilized (in the case of Heloderma), it wouldbe vulnerable to subsequent capture and poten-tial consumption. In this context, it makessense why Heloderma behave as they do whenthey bite and why they do not possess a more“efficient” venom system. What helodermatids


lack in their “crude” delivery system, however,they compensate for in a sophisticated array ofvenom constituents and bite tenacity. No doubt,the venom chemistry of Heloderma is efficientfor defensive purposes.

One might more appropriately ask: Why arethere not more lizards that use a venom systemfor defense? The answer might be that mostlizards can run away more effectively than theycan bite. However, there are rare cases wherebites of varanid lizards may produce symptomsof toxicity (Ballard and Antonio 2001). In atleast three cases, reptile keepers bitten byVaranus griseus, the Desert Monitor, showedsymptoms ranging from dysphagia (difficultyswallowing), tightness of the chest muscles,and dyspnea (labored respiration) to dizziness,facial pain, and muscle soreness (Ballard andAntonio 2001). Desert monitor lizards haveshown chewing motions during bites that maycontinue for over one minute. Whether thesesigns/symptoms are truly reactions to toxic pep-tides or proteins in the venom of Varanus needsto be thoroughly investigated.

Of the few other vertebrates known to use avenom system exclusively for defense, the Platy-pus (Ornithorhynchus anatinus) and Stonefish(Synanceja horrida) are noteworthy. Peptidesand other components in Platypus venom relaxsmooth muscle in rats, promote edema and in-flammation, and produce extreme pain (Fenneret al. 1992; De Plater et al. 1998). Stonefishvenom produces intense pain and induces hy-potension via relaxing smooth muscle in thewalls of blood vessels (Low et al. 1993). Thesevenoms act to repel and potentially immobi-lize potential predators with symptoms (severepain, inflammation, and hypotension) similarto those produced by bites of Heloderma. Spit-ting cobras seem to have evolved the ultimatevenom delivery system for defense. Venom isejected from the fangs as a jet that becomes afine spray (Bogert 1993). A tiny speck of AfricanSpitting Cobra, Naja nigricollis, venom landingin the eye produces a pain, in the words of aphotographer affected by the venom, greaterthan any ever experienced (Bogert 1993).

In contemporary helodermatid lizards, thevenom system functions as an effective defensemechanism, while some of the bioactive pep-tides in the venom could play a role in diges-tion. The venom proteins and peptides appearto act primarily on initiating a powerful inflam-matory/pain response, relaxing smooth muscle(which results in vasodilation and hypotension),and influencing energy metabolism. Taken to-gether, the venom constituents clearly act phys-iologically to immobilize or incapacitate the bitevictim. Some of these components not only pro-foundly affect the physiology of potential mam-malian adversaries, but they are, in a sense, partof their physiology. These venom componentsare analogues of important mammalian hor-mones, including serotonin, secretin, VIP, andGLP-1. The kallikrein enzymes are commonparticipants in the inflammatory response inmammals. As noted above, many of the bioac-tive peptides (helospectin and helodermin, inparticular) have been located, using immuno-histochemical techniques, in several mam-malian tissues including the brain, pancreas,blood, colon, lung, stomach, breast, heart, intes-tine, uterus, liver, urogenital system, and others(Raufman 1996). In these tissues, they appearin association with membrane receptors thatplay a role in regulating secretory activities andlocal blood flow. When they were first discov-ered, it was thought that some of the bioactivepeptides in Heloderma venom represented ho-mologues of mammalian hormones yet to bediscovered (Parker et al. 1984). This appears notto be the case; for example, helodermin andexendin-4 from Heloderma are not the evolution-ary precursors to mammalian VIP and GLP-1.They are distinct peptides encoded by differentgenes and, therefore, appear to have evolved in-dependently of the mammalian peptides theyresemble (Chen and Drucker 1997; Pohl andWank 1998). To find so many Heloderma venompeptide sequences within the tissues of mam-mals suggests an intricate example of biochemi-cal mimicry. The venomous bite of helodermatidlizards has apparently evolved to incapacitate anddeter an enemy with a diversity of toxins that



manipulate its physiology in a variety of ways. Anintriguing possibility also exists that exendin,and perhaps other bioactive peptides in thevenom of Gila Monsters and Beaded Lizards,may act to regulate the lizards’ own digestivephysiology (Young et al. 1999b). What has pre-viously been called a “primitive,” “crude,” or“inefficient” venom system appears, in fact,highly refined and effective.

Since the early 1980s, when many of the con-stituents of Heloderma venom were discovered,little attention has been directed at whole-venomphysiological effects. When taken as a whole,many of the venom components may show syn-ergistic consequences that are not apparentwhen examined alone. For example, gilatoxinshows greater toxicity when combined withother venom components than when actingalone (Tu 1991). It is likely that other venom con-stituents, especially the kinin-releasing peptidesand the bioactive peptides, may interact in simi-lar ways. Investigations into how the venomcomponents may interact with one another inmammalian tissues would be another fruitfularena for future research (chap. 10). A picture ofwhole-venom effects partially emerges by exam-ining the effects of Heloderma envenomation inhumans, which we consider next.

HUMAN ENVENOMATION BYHELODERMA: OVERVIEW OF BITE CASE HISTORIES

A rich, entertaining, and commonly erroneousliterature is associated with bite case histories ofHeloderma (see chap. 1). Vivid tales abound re-counting suffering, terror, and death. I havefound more exaggerated and erroneous infor-mation associated with this Heloderma topicthan with all others combined. Woodson (1947)provided one of the first summaries of the biteof Heloderma, reporting that 29 of 136 casesended in death. Bogert and Martín del Campo(1956) summarized 34 cases between the1880s and 1956, mostly from newspaper clip-pings and correspondence, eight of which al-legedly resulted in death. Both Woodson (1947)

and Bogert and Martín del Campo (1956) em-phasized that details regarding deaths fromHeloderma bites were often sketchy, contradic-tory, and invalidated, and that alcohol was in-volved in most cases. Russell and Bogert (1981)discussed the outcomes of another 16 cases, aswell other published records available to them(Shannon 1953; Bogert and Martín del Campo1956; Grant and Henderson 1957; Albritton etal. 1970; Stahnke et al. 1970). None of the 16cases mentioned by Russell and Bogert resultedin death. Since the dubious case in 1930 of anintoxicated pool-hall operator in Casa Grande,Arizona (chap. 1), there have been no authenti-cated reports of a death from the bite of Helo-derma suspectum. In fact, I have not even beenable to find any published validated cases of truly“legitimate” bites (i.e., victims being accidentallybitten by wild Gila Monsters that were not poked,picked up, handled, or otherwise harassed).

Hearsay and fertile imaginations have, there-fore, produced far more information about thebite of Heloderma than have scientific recordsand reports. Of the many bite cases reported innewspapers, correspondences, and the popularliterature since 1950, I could find only 17 thatwere based on firsthand information and pub-lished in peer-reviewed biological or medicaljournals (tables 7 and 8). Even in these cases, onedescription of a myocardial infarction followingthe bite of a Gila Monster (case no. 11, tables 7and 8) was published twice, by different authorsin 1988 and 1989 (Bou-Abboud and Kardassakis1988; Preston 1989). A summary of these bitesand their signs and symptoms are given in tables7 and 8. Since 1950, bites by Heloderma have be-come less newsworthy, so only the most seriousor noteworthy cases get reported in scientificjournals. Since 1981, I could find only 10 suchcases. Tables 7 and 8 do not include cases re-ported in the news media (unless they are alsopublished in a peer-reviewed journal), or thosecontained in unpublished hospital records, re-gional reports, etc. Tables 7 and 8 should be in-terpreted carefully, therefore, because, althoughthey contain some of the best-documented cases,they are not necessarily the most representative.


Nevertheless, an analysis of the cases sum-marized in tables 7 and 8 is instructive. Mostbites were to a finger or hand and came frompet Gila Monsters. These bites are more likely toproduce intense pain and local edema but areless likely to produce more serious symptomssuch as severe hypotension, cardiac and bloodabnormalities, or shock. All bites resulted fromcareless handling, some of which occurred dur-ing public demonstrations or classroom lec-tures. Alcohol was involved in some of the mostserious cases (Heitschel 1986; Piacentine et al.1986; Caravati and Hartsell 1994).

Based on an examination of case histories byBogert and Martín del Campo (1956), Russelland Bogert (1981), recent bite case reports(tables 7 and 8), and my knowledge of approxi-mately 30 unreported or untreated bites over re-cent years, the most common signs and symp-toms of Heloderma envenomation in humansare similar to those observed in other mammals(table 4). They include pain, local edema, and afeeling of weakness, faintness, or nausea.

Bleeding at the site of the bite may be profuse,not from anticoagulant effects of the venom,but from the lacerating effect of the teeth andtenacity of the bite (fig. 13). Pain, often severe,usually begins within minutes, and may lastseveral hours. The pain has been described as asteady burning, like a spine imbedded in theflesh. Pain may spread well beyond the site ofthe bite; a person bitten on the arm may feelpain from the shoulder to the hand. Edema(swelling) can occur within minutes and extendwell beyond the region of the bite (fig. 13).

A second set of relatively common symp-toms includes hypotension, sweating, an in-creased heart rate, and vomiting. Blood chem-istry changes, including elevated leukocytecount, reduced potassium levels, and reducedplatelets, are occasionally shown in moderatelysevere cases (tables 7 and 8). There is limited ev-idence that previous exposure to Heloderma bitesmay sensitize some individuals and result in anallergic reaction to the venom (Cantrell 2003).More severe cases seem to result from bites

TABLE 7 Heloderma Bite Cases Published in Peer-Reviewed Journals since 1950

case no. cause bite location references(all from careless handling)

1 Pet Finger Shannon 19532 Pet Finger Shannon 19533 Demonstration Finger Tinkham 19564 Demonstration Thumb Grant and Henderson 19575 Demonstration Finger Albritton et al. 19706 Demonstration Finger Stahnke et al. 19707 Pet Hand Roller 19778 Pet Abdomen Heitschel 19869 Wild capture Forearm Piacentine et al. 1986

10 Pet Hand Streiffer 198611 Wild capture Forearm Bou-Abboud and Kardassakis

1988 and Preston 198912 Recent capture Calf Caravati and Hartsell 199413 Wild capture? Thumb Caravati and Hartsell 199414 Pet Shoulder Caravati and Hartsell 199415 Wild capture Triceps Caravati and Hartsell 199416 Pet Finger Strimple et al. 199717 Pet Hand Cantrell 2003


located closer to the core of the victim’s body,such as the abdomen, shoulder, calf, or forearm(tables 7 and 8). The most severe cases result inextreme hypotension, which may be accompa-nied by life-threatening anaphylaxis (Piacentineet al. 1986), coagulopathy and acute myocardialinfarction (Bou-Abboud and Kardassakis 1988),or profuse diarrhea and lethargy (Heitschel1986). These cases likely illustrate the powerfulphysiological effects of the kallikrein-like andbioactive peptides found in Heloderma venom.

In the most serious case, a young womanhad hidden a Gila Monster under her sweaterand walked into a tavern, whereupon the lizardbit her on the abdomen. Her screams alerted barpatrons of her condition, and her boyfriend re-moved the lizard by severing its head. When shearrived at the hospital, the woman was nearlyincapacitated, showing severe pain, vomiting,and diarrhea. She remained in intensive care for

36 hours (Heitschel 1986). This case (the onlyfemale in the sample) is noteworthy because thevictim’s symptoms are similar to pancreaticcholera, a condition produced by VIP-secretingtumors and also known as WDHA (watery diar-rhea, hypokalemia, acidosis) syndrome (Conni-grave and Young 1996). Such symptoms may bean example of the action of VIP-like bioactivepeptides in Heloderma venom.

TREATMENT OF BITES

Bites by Heloderma may be increasing because,as captive-breeding techniques have improved,more people are keeping these lizards in pri-vate collections (chap. 8). The docile nature ofHeloderma kept in captivity often lulls theirhandlers into a dangerous habit of compla-cency. The vast majority of bites by heloder-matid lizards occur on the fingers or hands.

TABLE 8 Bite Signs/Symptoms and Their Frequency

cases reportingpercent (%) of cases (FROM TABLE 7)

Pain 82 1–3, 5–8, 10–13, 15–17Local edema/swelling 82 1–7, 9–11, 13, 15–17Weakness, faintness, dizziness 65 1, 3, 4, 6, 8, 11–13, 15–17Nausea 65 2, 3, 5–8, 10, 12, 14, 16–17Hypotension 47 6, 8–14Diaphoresis (sweating) 47 4, 8–11, 13, 16–17Tachycardia (elevated heart rate) 35 5, 8, 11, 12, 14, 15Vomiting 35 3, 5, 10, 12, 14, 17Leucocytosis (elevated WBC count) 29 6, 8, 11, 12, 17Hypesthesia (hypersensitivity around bite) 24 1, 2, 12, 16Reduced blood potassium levels 18 8, 9, 11Reduced platelets 18 8, 11, 17Cyanosis (bluish discoloration around bite) 13 3, 8Cardiac abnormalities 12 7, 11Swollen or painful lymph glands 12 10, 11Lethargy 12 8, 14Anaphylaxis 6–12 9, possibly 17Diarrhea 6 8Tinnitis (ringing in ears) 6 2Exophthalmia or periorbital hemorrhage 6 8Hypothermia 6 12Miosis (contraction of pupil) 6 14


Most of these pass on uneventfully and go un-reported (Miller 1995). Although a Helodermabite is very unlikely to be lethal to a healthyadult, it should nevertheless be considered a se-rious medical emergency. A common miscon-ception is that only the dentaries in the lowerjaw (and to a lesser extent the maxillaries in theupper jaw) can deliver sufficient venom tocause serious effects. This is not the case; sig-nificant symptoms can occur by a seeminglyminor “slashing” bite from even the premaxil-lary teeth toward the front of the mouth (Tin-kham 1956; Strimple et al. 1997).

When a person is bitten by a Heloderma, thefollowing first aid measures are recommended:

1. Remove the lizard as quickly as possible.The longer the lizard bites, the more venomit is able to deposit into the wound and themore likely the bite is to produce serioussymptoms. In mild bites, where only a foldof skin is bitten, it may be possible to simplyhold the lizard behind the jaws and carefullypull it away; in cases where the jaws aremore firmly attached, it may be necessary topour water on the lizard or to pry it off withpliers or some other device. A thin, flat leverinserted between the lower jaw and the fleshand turned 90 degrees may work to quicklyrelease the jaws. When Heloderma are force-fully removed from the bite site, as is often

required, teeth are usually pulled out and alaceration results (fig. 13). I do not recom-mend trying to remove the lizard by applyinga flame to its chin or by using dangeroussolvents such as gasoline (which have beenadvocated in the past). These measures onlyadd to the possibility that additional injury and pain will result.

2. Immediately remove any rings, bracelets, orother jewelry (including piercings). Thesearticles may cause complications as edema(swelling) develops.

3. The bitten part should be immobilized; alight cloth bandage and mild pressure maybe applied to control any bleeding.

4. The victim should be transported (by an-other person) to medical care as quickly aspossible and reassured that they will not die.

5. DO NOT apply stun guns, heat, or ice to the wound. DO NOT use tourniquets orconstriction bands of any kind nor make incisions to suck out venom.

Once the victim has arrived at the hospital,vital signs should be monitored immediately.One of the biggest dangers is shock/hypoten-sive crisis brought about by a rapid fall inblood pressure. This can be treated in the vic-tim by infusing electrolyte solutions and ad-ministering antishock drugs. Pain normally

FIGURE 13. Bite to the index fingerfrom a Heloderma suspectum. Thelaceration occurred as the GilaMonster was extracted from thefinger. Considerable edema thatcommonly occurs from Gila Mon-ster bites had already subsided whenthis photograph was taken two dayslater (photo by M.L. Gilbert).


peaks within 1 to 2 hours, but may linger fordays (Caravati and Hartsell 1994). It can bedifficult to relieve; analgesics and morphinehave been used effectively (Strimple et al.1997). Edema normally peaks within 2 to 4hours and resolves itself without special meas-ures within 72 hours. Because it is largely sub-cutaneous, edema has not been reported tocause compartment syndrome or neurologicalproblems. Depending on the severity of thebite, laboratory blood tests should be per-formed to assess the possibility of electrolyteimbalance, leukocytosis, and coagulopathy,which have been reported previously (see ta-bles 7 and 8). An electrocardiograph should beused to evaluate any heart anomalies; myo-cardial conduction disturbance (Roller 1977)and myocardial infarction (Bou-Abboud and

Kardassakis 1988) have been observed. Anti-histamines or corticosteroids are usually un-necessary because allergic reactions are rare,although one case of anaphylaxis has been re-ported (Piacentine et al. 1986). The woundshould be carefully inspected for any brokenteeth and thoroughly cleaned with antiseptic.Soft-tissue radiography is not sufficient to lo-cate broken teeth (Caravati and Hartsell1994). Antibiotics are routinely given, al-though tissue necrosis and infections are veryrare. Tetanus immunization should be up-dated if necessary. Most victims of Helodermaenvenomation are released from the hospitalwithin 24 hours and recover completelywithin 2 weeks. More severe cases may re-quire hospitalization up to 48 hours (e.g.,Heitschel 1986).

Heloderma - University of California Press · chosen for the Gila Monster because E.D. Cope suspected it was venomous (Cope 1869), but it was not until well into the twentieth century

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