Metabolic conversion as a pre-receptor control mechanism for lipophilic hormones

Page 1

Eur. J. Biochem. 268, 4113±4125 (2001) q FEBS 2001

R E V I E W A R T I C L E

Metabolic conversion as a pre-receptor control mechanismfor lipophilic hormones

Stefan Nobel1,2, Lars Abrahmsen1 and Udo Oppermann3

1Biovitrum AB, Division of Pharmaceuticals, Department of Assay Development and Screening, Stockholm, Sweden;2Unit for Biochemical Toxicology, Department of Biochemistry and Biophysics, Wallenberg Laboratory, University of Stockholm, Sweden;3Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden

The majority of physiological effects mediated by steroids,

retinoids and thyroids is accomplished by binding to

members of the nuclear receptor superfamily of ligand

activated transcription factors. The complex specific effects

of lipid hormones depend not only on receptor expression,

distribution and interactions, but also on the availability and

metabolic conversion of the hormone itself. The cell-

specific metabolic activation of inactive hormone precur-

sors introduces a further level of hormonal regulation, and

constitutes an important concept in endocrinology. The

metabolic reactions carried out are achieved by dehydro-

genases/reductases, hydroxylases and other enzymes, acting

on ligands of the steroid/thyroid/retinoic hormone receptor

superfamily. The concept implies that these tissue- and cell-

specific metabolic conversions contribute to lipid hormone

action, thus pointing to novel targets in drug development.

All components of this signalling system, the hormone

compounds, the receptor proteins, and modifying enzyme

families originate from an early metazoan date, emphasiz-

ing the essential nature of all elements for development and

diversification of vertebrate life.

Keywords: hormone metabolism; hydroxysteroid dehydro-

genase, nuclear receptor, steroid, thyroid hormone, retinoid,

DHEA, short-chain dehydrogenases/reductases

I N T R O D U C T I O N

Lipid hormones represent chemically distinct classes ofmolecules mediating a multitude of essential effects invertebrates and mammals, including control of develop-ment, behaviour, metabolism, reproduction, electrolytebalance, cardiovascular tone, regulation of the immunesystem and inflammatory response. The main mammaliancompounds of importance can be classified as steroids,thyroid hormones and retinoids (Fig. 1).

Significant progress in the understanding of the mol-ecular action of lipid hormones has been achieved in thepast decades. It has been established that most of their

effects are achieved through binding to intracellular recep-tors [1±5], although, several important responses areachieved through binding to plasma membrane components[6]. The characterization of members of the nuclearreceptor superfamily and their associated cellular coregu-lators [1±5,7±11] has resulted in a wealth of informationregarding how lipid hormones accomplish their specificcellular functions. Association of the receptor withmembers of the same superfamily, i.e. heterodimerization,and interaction with other transcription factors, such asNF-kB, AP-1 or members of the STAT family, add anotherdimension of molecular operations, contributing to thetissue-specific effects of this group of hormones [12±17].Furthermore, work on hormone-response elements (HREs;cognate regulatory DNA sequences) has contributed to asimilar extent to our current understanding of the mechan-ism of action [1,2]. A further level of regulation oftranscriptional activity is added by interactions with othersignal transduction systems, e.g. peptide growth factors,through existence of phosphorylation sites in nuclearreceptors [18,19].

It was recognized more than four decades ago that steroidhormones exist in active or inactive forms and that thesecan be enzymatically interconverted, exemplified by thenonreceptor binding compound estrone and the active hor-mone estradiol, binding to the estrogen receptor (Fig. 1).Primarily regarded as an effect of catabolic reactions, thecorresponding inactive metabolites were later considered asprecursors, which can be activated in a tissue-specificmanner. This concept was established for androgens andestrogens, and coined intracrinology [20±22]. Clearly, this

Correspondence to U. Oppermann, Medical Biochemistry and

Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.

Tel.: 1 46 87287680, E-mail: [email protected]

Abbreviations: HSD, hydroxysteroid dehydrogenase; AKR, aldo-keto

reductase; SDR, short-chain dehydrogenases/reductases; HRE,

hormone response element; GR, glucocorticoid receptor; MR,

mineralocorticoid receptor; CYP, cytochrome P450; DHEA,

dehydroepiandrosterone; AME, apparent mineralocorticoid excess;

SULT, sulfotransferase; GABA, g-aminobutyric acid; VDR, vitamin D

receptor; RXR, retinoid receptor X; RA, retinoic acid; CRBP, cellular

retinol binding protein; CRABP, cellular retinoic acid binding protein;

ALDH, aldehyde dehydrogenase; ADH, alcohol dehydrogenase; SDR,

short-chain dehydrogenase/reductase; T3, 3,5,3 0-tri-iodothyronine; T4

or thyroxine, 3,5,3 0,5 0-tetra-iodothyronine; PGG2, prostaglandin G2;

COX, cycloxygenase.

(Received 6 March 2001, revised 3 May 2001, accepted 18 June 2001)

Page 2

idea adds a further mechanistic principle to hormonephysiology, and implies that metabolic conversion comple-ments the cascade of ligand-binding to the receptor andassociated regulatory transcriptional events, as outlined inFig. 2.

The aim of this review is to demonstrate by selectedexamples, that enzymatic regulation of active hormones,constitutes a prereceptor control (`switch') mechanism,which is a common theme along the different classes oflipid hormones, and which is not restricted to specificsteroid hormones. The majority of these prereceptorregulatory enzymes are NAD(P)(H) dependent hydroxy-steroid dehydrogenases (HSDs). At present, all HSDsprincipally involved in hormone metabolism belong toeither the short-chain dehydrogenase/reductase (SDR)superfamily [23,24], or to the aldo-keto reductase (AKR)superfamily [25]. Additional enzymes involved in hormonemetabolism belong to different classes of oxidoreductases,e.g. cytochrome P450 (CYP) enzymes and different con-jugating phase II enzymes [26]. However, these reactionsmostly constitute irreversible transformations involved insynthetic or catabolic pathways.

H O R M O N E S Y N T H E S I S

There are important differences in the synthetic routes ofthe various lipophilic hormones and vitamins. Chemically,the different steroid hormones, including vitamin D, andretinoids are isoprene condensation products, whereasthyroids are derivatives of the amino acid tyrosine.

In mammals, the location of steroid hormone synthesisdepends on the class of hormone. These production sites aremainly the `classical' endocrine glands, such as adrenal,gonads, uterus and placenta, although important species andgender differences exist. However, auto- or paracrinesynthesis of steroids in `nonclassical endocrine' organs,e.g. brain, heart or thymus, has been reported [27±29].Furthermore, tissue-specific expression of critical keymetabolic enzymes creates the possibility to regulatelocally the amount of available hormone from circulatingprecursors.

The different biosynthetic routes leading to the definedclasses of steroid hormones are performed predominantlyby distinct oxidases and oxidoreductases of the cytochromeP450 and SDR superfamilies (reviewed in [26]). Different

Fig. 1. Lipid hormones and some metabolic conversion routes as discussed in this text. Receptor ligands of different hormone classes are

highlighted by grey boxes. Double arrows indicate reversible steps, carried out by different isozymes or different enzyme classes, whereas bold,

single-headed arrows point to `irreversible' reactions. Enzymes are indicated by numbers as follows: 1, steroid sulfatase; 2, steroid sulfotransferase;

3, 3b-hydroxysteroid dehydrogenase/D4,5 isomerase; 4, 17b-hydroxysteroid dehydrogenase; 5, 5a-reductase; 6, 3a-hydroxysteroid dehydrogenase;

7, 11b-hydroxysteroid dehydrogenase; 8, 20a-hydroxysteroid dehydrogenase; 9, retinaldehyde dehydrogenase; 10, retinol dehydrogenase

4114 S. Nobel et al. (Eur. J. Biochem. 268) q FEBS 2001

Page 3

inborn errors of metabolism, caused by mutations insynthetic enzymes are now well established, emphasizingthe critical role of steroids in mammalian physiology anddevelopment [26,30,31]. Of further importance, in humansand other primates, is the extra-gonadal and extra-placentalexpression of key enzymes such as steroid sulfatase,3bHSD/D4,5 isomerase, 17b-HSD isozymes and CYP19(aromatase), e.g. in breast tissue, to locally produce bothandrogen and estrogen hormones [20±22] from theadrenal precursors dehydroepiandrosterone (DHEA) andits sulfonate ester dehydroepiandrosterone sulfate(DHEA-S).

S T E R O I D H O R M O N E M E T A B O L I S M

Only steroids displaying distinct structural properties act asligands by binding to the different nuclear receptors. Forexample, a nearly planar steroid ring structure and a 3-oxoconfiguration are common denominators of glucocorticoid,mineralocorticoid, progesterone, estrogen and androgenhormones for succesful association with their respectivereceptors. Metabolic transformations of these chemicalconfigurations therefore have a profound effect on receptorbinding, e.g. loss of the planar structure by 5b reduction ofdouble bonds at C5 results in complete loss of receptor

association of steroid hormones, while reduction of the3-oxo group to 3a or 3b hydroxyls leads to reduced bindingproperties. There are further specific reactions for inactivat-ing active steroid hormones. Besides reduction of doublebonds these comprise hydroxylation, subsequent conjuga-tion (e.g. with sulfate or glucuronic acid) and furtheroxidoreductive reactions. Reduction of C4±5 or C5±6double bonds to the 5a or 5b isomers are virtually irre-versible reactions in mammals, while many other reactionsmust be regarded as `biologically reversible'. Tissue-specific expression of enzymes catalyzing a reversion ofreaction leads to an intricate balance or `shuttle', allowingspecific regulation of steroid ligand availability. Several ofthese pairs of `switch' mechanisms are discussed in thefollowing sections.

G L U C O C O R T I C O I D S A N DM I N E R A L O C O R T I C O I D S

In humans, the adrenal glands secrete three different classesof steroids; glucocorticoids, mineralocorticoids and andro-gens (mainly the sex steroid precursors DHEA and itssulfonated derivative DHEA-S, see below). The glucocorti-coids (cortisol in man and most mammals, corticosteronein rodents and lower vertebrates) exert potent effects oncellular function in essentially all organ systems. Theeffects include regulation of carbohydrate and amino-acidmetabolism, maintenance of blood pressure, modulation ofthe stress and inflammatory responses [32], maturation offetal organ systems and metabolic adaptation during preg-nancy [33]. In contrast to this broad range of effects,mineralocorticoids (in humans mainly aldosterone) primar-ily affect the extracellular balance of sodium and potassiumin target tissues such as kidney, colon and salivary glands[34,35].

The hydroxyl group at C11 is critical for cortisol to exertits biological effect, i.e. is necessary for cortisol to bindto the glucocorticoid receptor (GR). The GR and themineralocorticoid receptor (MR) share 57% and 96%amino-acid identities in steroid and DNA binding domains,respectively [36,37]. The mineralocorticoid hormone aldo-sterone binds only to MR with high affinity (Kd 1 nm). Incontrast, cortisol/corticosterone have nanomolar affinity forboth receptors and interact stronger with MR (Kd 1 nmcompared to 10 nm for GR). Despite this high affinity,cortisol/corticosterone do not bind to the MR in mineralo-corticoid target tissues (e.g. kidney, colon, salivary glands).The reason is local inactivation by oxidation of the C11hydroxyl group (dehydrogenation), catalyzed by the enzyme11b-hydroxysteroid dehydrogenase 2 (11b-HSD2). Theimportant function of 11b-HSD2 to protect MR frominappropriate activation by cortisol/corticosterone is clearlyillustrated in the syndrome of apparent mineralocorticoidexcess (AME), associated with hypertension and hypokal-emia caused by inactivating mutations in the 11b-HSD2gene [[38,39]. As expected, mice with a deleted 11b-HSD2gene develop hypertension [40]. However, the role of11b-HSD2 is not exclusively to protect MR, demonstratedby its important role in the placenta protecting the fetusagainst high levels of maternal glucocorticoids [33]. Somenonepithelial tissues have MR but lack 11b-HSD2. Here,not fully characterized mechanisms lead to different effectsfrom glucocorticoid or aldosterone binding to the MR [41].

Fig. 2. Principle of local lipophilic hormone regulation (steroids,

retinoids and thyroid hormones). Model of regulation of local

hormone concentration, representing a `shuttle' system between active

hormone (HA) and inactive hormone (HI), mediated by tissue-specific

metabolizing enzymes (activating, Ea, and inactivating, Ei). The

occurrence of these enzymes determines the hormonal responsiveness

of the particular cell. Note that opposing enzymes may not be localized

within the same cell. Plasma binding proteins exist for different types

of ligands, e.g. CBG (corticosteroid binding globulin) selectively

binding cortisol, thereby influencing the level of `free' hormone, which

can enter the cell. NR � nuclear receptor.

q FEBS 2001 Enzymatic control of lipid hormones (Eur. J. Biochem. 268) 4115

Page 4

In the hippocampus, MR and GR coexist and monitorcortisol/corticosterone levels; due to the higher affinity, theformer is occupied at basal levels of glucocorticoid, whilethe latter is only occupied at peak levels [42].

Peripheral formation of glucocorticoids has gained con-siderable attention over the last few years, as activation ofcortisone by 11-oxo reduction to cortisol has been shown tooccur in several peripheral tissues (reviewed in [43]). Thisreaction is catalyzed by 11b-hydroxysteroid dehydrogenasetype 1 (11b-HSD1), initially believed to be the inactivatingenzyme involved in AME (above), but later shown tofunction as an 11-oxo-reductase in vivo [44]. This isoformis coexpressed in most tissues with GR (primarily liver,omental fat, gonads, brain, skeletal muscle and vasculature[45]). Gene-deletion experiments in mouse indicate that thisenzyme is important both for maintenance of normal serumcortisol levels, and for upregulation of key hepatic gluco-neogenic enzymes [46]. Clinical observations of deficiencyin cortisone activation have been made [47,48], although sofar no clear evidence for a primary deficiency of 11b-HSD1has been reported [49,50]. However, there are severalclinical indications for a role of 11b-HSD1 in maintainingcortisol action, and therefore it has been postulated that11b-HSD1 has a role in the etiology of insulin resistance[51] and control of insulin secretion [52].

Thus, to date two enzymes have been identified whichmediate interconversion between cortisol and cortisone,each enzyme irreversible in vivo and together yielding`biological reversibility'. The ratio of cortisol to cortisonein circulation is determined by the balance between theactivities of those two enzymes, mainly 11b-HSD1 in liverand 11b-HSD2 in kidney. Yet, the important principle isthat the corticosteroid action upon individual target cells isdetermined by the enzyme action within the cells and notby the circulating steroid levels alone.

D H E A A N D D H E A - S

In humans, sex steroids are synthesized in peripheral orgonadal tissues: a substantial amount (up to 30±50% oftotal androgens in males) are produced by extragonadalconversion of inactive precursors, and in females peripheralestrogen formation might be even more important [21]. Theprecursor steroids DHEA and to a lower extent pregneno-lone, and its sulfonated derivatives DHEA-S and pregne-nolone-S are secreted from the adrenals in large amounts, aunique feature for humans and other higher primates. Asubstantial reduction (70±95%) in the formation of DHEAand DHEA-S occurs during ageing in parallel to a reductionof sex steroid levels [53]. This is the background to promoteDHEA as a youth drug, although at present the quantitativeimportance of plasma DHEA as a precursor for testosteroneand estradiol is poorly understood. DHEA-S is consideredas an inactive reservoir of DHEA, which is locally con-verted by enzymatic removal of the sulfonate prior tofurther conversion to steroid hormones [54]. Furthermore,kinetic parameters such as binding of sulfoconjugates toplasma proteins, hepatic and urinary clearance, prolongserum half-life by two orders of magnitude [55]. Severalenzymes of the sulfotransferase (SULT) and sulfatasefamilies are involved in either addition or removal of thesulfonate group, together forming another example ofbiological reversibility or `switch' [56±58]. Sulfonation of

steroids may also function as a trapping mechanism for theintracellular storage of steroid hormone or precursors, e.g.in steroidogenic tissues such as the adrenal cortex wheresulfotransferases are highly expressed [59].

A N D R O G E N S A N D E S T R O G E N S

Active androgens and estrogens are in the 17b-hydroxyconfiguration, whereas the 17-oxo derivatives are notbinding to androgen and estrogen receptors, respectively.The conversion between the inactive and the active forms(estradiol/estrone and testosterone/androstenedione) is cata-lyzed by differentially expressed isozymes belonging to the17b-hydroxysteroid dehydrogenase (17b-HSD) family. Spa-tial and temporal activation and deactivation, is achieved byisozymes that display distinct reaction directions in vivo.Mostly, gonadal tissues convert 17-oxo steroids to17-hydroxy steroids, while the opposite holds true formany extragonadal tissues. The different isoforms within agiven species share less than 30% identity, while theorthologs are 70% or more identical, facilitating identifica-tion and consistent nomenclature in different species. Todate, 11 different 17b-HSD isoenzymes have been charac-terized (Table 1). However, the identification of the in vivo-relevant reaction is not always straightforward, as most17b-HSDs are able to catalyze the reversible reactionsin vitro [60]. Furthermore, several 17b-HSDs display broadsubstrate specificities, e.g. with progestins, retinoids, xeno-biotics and fatty acids, which makes the identification ofthe in vivo role a challenging task [61], further exemplifiedby 17b-HSD isoforms 4 and 9 [60] (see below). Phylo-genetic analysis indicates that enzymes regulating accessof active estrogens and androgens (i.e. 17b-HSD2 and17b-HSD6) are related to retinoid converting enzymes inC. elegans [62], the latter displaying 65% sequence identityto retinol dehydrogenase type 1.

Fig. 3. Steroid conversions involved in local estrogen activation in

breast tissue. The enzymes involved are indicated by numbers: 1,

steroid sulfatase; 2, steroid sulfotransferase; 3, 3b-HSD/ketosteroid

isomerase; 4, aromatase (CYP 19); 5. Estrone sulfotransferase; 6,

estrogen sulfatase; 7, 17b-HSD1; 8. 17b-HSD2 and 17b-HSD4.

DHEA-S, estrone-S and estradiol-S indicate the sulfonated derivatives.

4116 S. Nobel et al. (Eur. J. Biochem. 268) q FEBS 2001

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The role of temporally and spatially differentiatedexpression is demonstrated by the estrous cycle in rodents,during which at least four different 17b-HSD isozymes areexpressed. 17b-HSD1 is found in granulosa cells ofdeveloping follicles, activating estrone to estradiol. Thereductive 17b-HSD2 is expressed in epithelial endometrialcells. The type 7 isoform is responsible for local estradiolbiosynthesis in luteinized cells, while 17b-HSD8 sup-posedly has an inactivating role in the cumulus cells of theovary [22,63].

Furthermore, 17b-HSD1 catalyzes formation of estradiolfrom estrone in breast tissue. This local estradiol productionis important for tumor growth, making the enzyme anattractive target for inhibitor development [20]. A similarrole has been suggested for 17b-HSD4 in colonic cancer,where malignant biopsy material displayed an alteredactivity of this isozyme [64]. Local estrogen formationcan also be reduced by blocking the CYP19 (cytochromeP450 aromatase) mediated production of estrone fromandrostenedione [65]. Importantly, estradiol can be inacti-vated in a tissue-specific manner by sulfonation viaestrogen sulfotransferase catalyzed transfer of a sulfonateradical to the 3-hydroxy group. A mechanistic principle wassuggested by recent data, implicating that the estrogenactivity of hydroxylated polychlorinated biphenyls is due toinhibition of estrogen sulfotransferase, resulting in increasedestrogenic activity [66]. The sulfonate group can beenzymatically removed by estrogen sulfatase, providinganother mechanism to regulate local estradiol concentration[57]. Further metabolic alterations, e.g. change in redoxstate have a profound effect on steroid profiles and clinicalimplications have been suggested [67±69]. Figure 3 sum-marizes the reaction pathways centering around estradiol,e.g. in breast tissue and illustrates the importance ofisozymes in control of active hormone level.

The intracrine formation of active androgens in prostateand testes is essential for development of the male genitaltract [22]. 17b-HSD3, converting androstenedione intotestosterone, is almost exclusively expressed in testes, anddeficiency during fetal development leads to male pseudo-hermaphroditism [31]. Another genetic defect leading tomale pseudohermaphroditism is deficiency in steroid5a-reductase type 2, catalyzing the formation of theessential androgen dihydrotestosterone [70]. Due to thisisoform the ratio between testosterone and dihydrotesto-sterone is 1 : 10 in prostate, in contrast to the ratio of 10 : 1in plasma. However, 5a-reductase inhibitors, of use to treatboth benign prostate hyperplasia and prostate cancer,should display overlapping inhibition characteristics againsttype 1 and 2 isozymes. This is demonstrated by the widelyused inhibitor finasteride, which only modestly decreasesclinical signs, likely due to lack of type 1 5a-reductaseinhibition [70]. The situation is rendered more complexthrough metabolic pathways involving 3a-HSD isozymes,mostly belonging to the AKR superfamily, with a distinctand specific expression and isozyme pattern, leading toan androgen shuttle between active and inactive forms[71±73].

P R O G E S T I N S

The progestin progesterone is required to support gestationin humans, and is synthesized initially by the corpus luteum

and during term by the placenta. Chemical abortion, such astreatment with the progesterone antagonist mifepristine(RU486) prevents ovulation by inducing luteolysis andpremature menstruation. In many but not all species,progesterone is essential for maintaining pregnancy, andaccordingly, metabolism to the weaker progestin 20a-hydroxy progesterone by 20a-HSD can be associated withtermination of luteal and placental stage pregnancy[74±77], indicating that 20a-HSD works as a progestin`switch' in a species-specific manner. In testis or theadrenals, the major substrates for 20a-HSD may be17a-hydroxypregnenolone or 17a-hydroxy progesterone,leading to 20a-OH steroids. These are not substrates for theCYP450 17,20-lyase and thus cannot be converted intoprecursors of androgens and estrogens, in contrast to theparent steroids. A novel role for progesterone metabolizingenzymes, such as 20a-HSD, has been postulated in theprotection of MR against high levels of progesterone [78],similar in concept as the role of 11b-HSD2 in the MRprotection against cortisol occupancy.

Several 20a-HSD isoforms have been identified thus far[60]. The ovarian 20a-HSDs characterized display high-sequence similarity to cytosolic rat liver 3a-HSD, and thusare members of the AKR superfamily [79]. Again, theoverlapping substrate specificities of 17b-HSD1 and17bHSD2 suggest roles in 20a-OH metabolism ofprogestins. 17b-HSD1 inactivates progesterone while17b-HSD2 converts 20a-hydroxyprogesterone to proges-terone, contributing to the estrogen- and progestin-dependentregulation of endometrial growth [60]. However, it isanticipated that further forms exist [76,80].

N E U R O S T E R O I D S

The concept of local activation and inactivation reactionstakes another twist in the brain, where steroids havemodulating functions in addition to their role as ligands ofnuclear receptors (reviewed in [81]). It has long beenknown that steroids have multiple effects on nerve cells.Initially, it was postulated that these steroids weresynthesized peripherally by endocrine glands, until theirsynthesis in the brain was detected by Baulieu andcoworkers [82]. The term `neurosteroids' has been coinedto designate steroids synthesized from cholesterol or otherprecursors in the nervous system. Neurosteroids allosteri-cally modulate the affinity of receptors of several types,including N-methyl-d-aspartate receptors, nicotinic recep-tors and g-aminobutyric acid (GABA)A receptors. Forexample nanomolar concentrations of tetrahydrosteroidsincrease the affinity of the GABAA receptor for GABA[83]. These tetrahydrosteroids are locally formed from5a-reduced steroids (e.g. 5a,3a-tetrahydroprogesteronefrom 5a-dihydroprogesterone) by 3a-HSD. This is sup-ported by recent results, indicating that changes in thesensitivity of GABAA receptor are associated with fluctu-ations in endogenous levels of progesterone and 5a-dihydroprogesterone, occuring during the menstrual cycleand pregnancy [84]. This effect may be responsible forsome of the pre±menstrual syndrome symptoms [84]. Inaddition to the modulation of GABAA affinity by tetra-hydrosteroids, a decreased affinity of GABAA receptors bysulfoconjugates of pregnenolone and DHEA has beenreported [85]. However, signalling through other receptor

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types, e.g. the oxytocin receptor, is also modulated bypregnane derivatives [86] again demonstrating the complexinterplay between peptide and steroid ligands. An addi-tional role of neurosteroids in regulation of tubulin poly-merization was recently reported [87]. In summary, steroidslocally produced in brain are involved in the control ofmetabolic, behavioral, and psychical processes includingcognition, stress, anxiety and sleep [83,85].

V I T A M I N D

Vitamin D was identified as the antirachitic principle inrickets. It plays a central role in calcium and phosphatehomeostasis, and is essential for the development andmaintenance of osseous tissue [88]. The isolation of fat-soluble, antirachitic components in, e.g. fish-oil, and thediscovery of photolytic cleavage of 7-dehydrocholesterolby UV light, led to the elucidation of vitamin D synthesisand structures. Several natural, dietary compounds werefound to display biological activity, e.g. ergocalciferol(vitamin D2) and cholecalciferol (vitamin D3). Both areformed by formation of secosteroids through pericyclic UVcleavage of steroid ring B, a reaction occuring in the skin.Further research led to the identification of more potentcompounds. This activation is achieved through 25-hydroxylation of the steroid alkyl-side chain [25-(OH)D3],and further 1a-hydroxylation, to yield 1,25-dihydroxyvitaminD3 [1,25(OH)2,3]. These reactions are cytochrome P450-mediated, predominantly occuring in liver and kidney,respectively [89]. The discovery of the vitamin D receptor(VDR) and its heterodimerization with retinoid receptor X(RXR), the complex interactions with coactivators, andexpression of enzymes involved in vitamin D3 synthesis,has resulted in a detailed picture of vitamin D action [88]. Itis now accepted that vitamin D effects are not onlyrestricted to `classical' target tissues, such as bone, kidneyand intestine, but also play important roles in `nonclassical'target tissues, such as skin, pancreas, muscle, hematopoieticand malignant cells, the nervous system and the immunesystem [88,90,91]. Besides the `classical' regulation ofcalcium and phosphate metabolism [92], these `nonclassical'effects include antiproliferative and prodifferentiatingactions in hematopoietic cells and suppression of theimmune system (similar to glucocorticoids) by shifting theTh1/Th2 thymocyte balance [93±95]. One example of localhormone regulation is the expression of 1a-hydroxylase inactivated macrophages [90] which results in local activationand potentiation of 25(OH)D3 effects, leading to altereddifferentiation and maturation of monocytes.

R E T I N O I D S

For many years, naturally occuring retinoids and theiractive metabolites have been recognized as essential mol-ecules regulating growth, reproduction, vision, resistance toinfection, as well as being associated with schizophrenia[96±99]. Retinoic acid (RA) directs a variety of essentialbiological effects by modulating gene expression duringdevelopment and postnatally, to control differentiation orcell-death of numerous cell types in several organs [96,98].Retinoids are stored as retinyl esters, and transported byseveral classes of binding proteins, emphasizing that themajority of cellular retinoids exist as protein-bound

molecules. The binding proteins consist of cellular retinolbinding protein (CRBP) and cellular retinoic acid bindingprotein (CRABP), which together with the retinoid forms atight hormone-binding protein `cassette' [98,100]. Afterhydrolysis of esterified forms, retinol (vitamin A) under-goes metabolic activation by dehydrogenation into retinal(carried out by retinol dehydrogenases), followed by irre-versible oxidation into the active hormone RA (performedby retinaldehyde dehydrogenases), a metabolic route resemb-ling the pathway of ethanol oxidation to acetaldehyde andacetic acid in mammals. Indeed, all steps in RA synthesiscan be catalyzed by several isozymes of the aldehydedehydrogenase (ALDH) and alcohol dehydrogenase (ADH/medium chain dehydrogenase reductase) superfamilies[101,102], at least in vitro using unbound retinoids. Inlight of the tight binding to CRBP/CRABP, the enzymesresponsible for retinoid acid metabolism in vivo are con-sidered to metabolize protein-bound retinoids [98],although this point is at present insufficiently understood.CRBP deficient mice show normal retinoid metabolism[103], whereas deletion of class I and IV ADH in micesuggest a role of these isozymes in retinol metabolism[104,105]. Several further cytosolic and microsomal retinoldehydrogenases have now been identified to catalyze theCRBP-bound retinol dehydrogenase reaction [98], thusconstituting an important regulatory mechanism. At least 10different cDNA clones from rodent and human species havebeen isolated, all of which encode microsomal members ofthe short-chain dehydrogenase/reductase (SDR) superfamily[23,98,106], and which catalyze the conversion of all-transretinol or various cis-retinol isomers into the correspondingretinals. Notably, most of these enzymes display multiple, tosome extent species-dependent substrate specificities, e.g. as3a-hydroxysteroid dehydrogenases in steroid hormone meta-bolism [98,107±109], thereby adding a further link betweensteroid and retinoid hormone pathways (see Table 1).

The two major aldehyde dehydrogenases involved in theirreversible oxidation to the retinoic acids are members ofthe aldehyde dehydrogenase superfamily [110]. Furtherreactions, mainly leading to inactive metabolites are carriedout by different enzymes of the cytochrome P450 super-family [98]. Some purified enzymes of this family catalyzethe conversion of retinol into retinal (similar to some CYPmediated hydroxysteroid dehydrogenase activities) and ofretinal into retinoic acid, but with unfavourable kineticconstants, suggesting that these CYP mediated reactions donot significantly, if at all, contribute to a retinoid `shuttle'metabolism in vivo.

T H Y R O I D H O R M O N E S

Thyroid hormones regulate essential functions duringdevelopment and normal life in most organs. The majorproducts secreted from the thyroid gland are 3,5,3 0-tri-iodothyronine (T3) and 3,5,3 0,5 0-tetra-iodothyronine (T4;thyroxine). Thyroxine is < 8- to 10-fold more abundant inthe thyroidal secretion, but the thyroid hormone receptorbinds T3 with a 10-fold higher affinity compared to T4.Approximately 85% of the secreted T4 is metabolizedperipherally to the active hormone T3 and the inactivecompound `reverse T3' (3,3 0,5 0-tri-iodo-thyronine, rT3),catalyzed by iodothyronine 5 0deiodinase (5 0D) isozymes(see Table 1, Fig. 1) [111]. These enzymes belong to a

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recently identified family of eukaryotic selenoproteins[112±115], which thus far comprises three distinctisozymes. These enzymes display a spatial and temporaltissue-specific expression pattern and consequently, areinvolved in local activation or inactivation of this class oflipophilic hormones. Type I deiodinase (5 0D-I) primarilyinactivates sulfated thyronines, whereas type II deiodinase(5-D-II) catalyzes the activation step from T4 to T3, and ishighly expressed in fetal and adult brain, heart, skeletalmuscle and placenta. Interestingly, 5-D-II activity appa-rently is important to maintain adequate T3 levels not onlyunder basal conditions, but also under limiting amounts ofT4, as often observed under iodine deficiencies [112,116].Type 3 deiodinase (5 0-D-III) is considered to be a hormoneinactivating enzyme as it converts T4 and T3 to theirinactive metabolites (reverse T3 and 3,3 0-di-iodothyronine,respectively). Thus, the expression pattern of these iso-zymes in addition to other thyronine modifying enzymes(e.g. sulfatases and sulfotransferases) dictates to an appre-ciable extent the tissue-specific action of thyroid hormones[112,117].

A R A C H I D O N I C A C I D D E R I V A T I V E S

Eicosanoids, derived from arachidonic acid, are a group oflipid mediators distinct from the lipid hormones bothchemically and by the signal transduction they convey.These short-lived compounds are formed locally and exert aparacrine or autocrine mode of action, mostly mediatedthrough receptors located in the plasma membrane.However, some actions are mediated through members ofthe nuclear receptor family [4] and some metabolic stepsshow a similar pattern as the steroid `shuttle' systems.

Eicosanoids play essential roles in, e.g. inflammatoryprocesses, and form the main distinct classes of prosta-glandins, thromboxanes, leukotrienes and lipoxins [118].Upon release from phospholipids by phospholipases,arachidonic acid is converted into prostaglandin G2(PGG2) by two different types of cyclooxygenases(COX1 and COX2) [118,119]. This intermediate serves asstarting point for the synthesis of all classes of prostaglan-dins (either nonenzymatically or catalyzed through distinctPG synthases) and for the synthesis of thromboxanes(through thromboxane synthase). Leukotrienes are derivedfrom arachidonic acid via 5-lipoxygenase to form theendoperoxide LTA4, which is an intermediate for formationof LTB4 (via LTA4 hydrolase), and glutathione adducts viaglutathione transfer. These pathways involve mostly irre-versible nonenzymatic and enzyme-mediated steps. How-ever, several dehydrogenase and reductase reactions are ofconsiderable importance, mainly in the metabolism ofprostaglandins. Among the multitude of reactions possible,the oxidation at the 15-OH group of prostaglandins leads toinactive metabolites. This reaction is catalyzed by distinctNAD(P)1-dependent prostaglandin dehydrogenases, belong-ing to the SDR superfamily [120,121]. Several attempts todevelop 15-OH prostaglandin dehydrogenase antagonists,useful as antiulcer, antithrombotic or anticancer agents havebeen initiated, however, mainly are discontinued.

Another enzyme of interest, the NADPH-dependentenzyme 11-ketoreductase, is involved in the stereospecifictransformation of PGD2 to the metabolite 9a, 11b-PGF2.In humans, this enzyme has been found mainly in liver and

lung [122]. Interestingly, the 9a, 11b-PGF2 compoundshows a different activity profile, and has been found tomediate contraction of bronchial smooth muscle, coronaryarteries, to inhibit platelet aggregation, to induce natriuresisand to be a vasopressor substance [122].

E V O L U T I O N O F H O R M O N EM E T A B O L I S M A N D R E C E P T O RP A T H W A Y S

As outlined above, signalling via lipid hormones andmediators and its biotransformation processes complementeach other in the common mechanistic principle of generegulation. All components of the systems described havedistinct phylogenetic roots and evolved separately, reflect-ing the transition of xenobiotics to become membranecomponents, ligands for binding proteins, or substrates formetabolizing enzymes [123±125]. This is clearly exempli-fied in the case of steroids. These molecules were probablyfirst formed in a period when sufficient oxygen was presentin the atmosphere, as the synthesis of cholesterol is strictlydependent on the occurrence of oxygen. These cholesterolderivatives might have served as components to regulatemembrane fluidity and then adapted to intracellular signal-ling molecules, either by binding to receptors or byformation of other signalling mechanisms, such as raftlipid microdomains [126]. At the same time, membranesteroids might have interacted with membrane molecules,reflected by the fact that certain effects can be modulatedthrough membrane receptors. In line with this suggestion isthe fact that steroids are mainly absent in bacteria orarchaea. However, the occurrence of steroids required thepresence of enzymes, capable of performing the essentialsynthetic reactions. It appears likely that these enzymeswere initially involved in xenobiotic metabolism and trans-formed into ligand-controlling `switches' with the emer-gence of receptor proteins. This is supported by the the factthat the main enzyme families involved in these trans-formation reactions, the CypP450, AKR and SDR familiesare evolutionarily old and are found in all forms of life[23,79,124,127,128]. Apparently, these enzyme familiesconstitute the oldest component of the describedbiotransformation-steroid hormone-nuclear receptor signal-ling system. However, similar functions as in highereukaryots, i.e. modulation of signalling molecules, arealso found in certain bacteria, e.g. in Rhizobia±plantinteractions requiring the SDR enzyme NodG [129].

With the occurrence of intracellular binding proteins,a transition from membrane interaction to intracellularliganding and DNA binding probably occurred. This view isconsistent with observations dating the appearence ofnuclear receptors to early metazoan life. At this time, thebasic components of the transcription machinery hadevolved, allowing to impose a regulatory system such astranscription factors. Subsequently, gene duplication, trans-fer and mutational events allowed cellular life to adapt tomany different conditions and environmental compounds[123,130].

C O N C L U S I O N S A N D P E R S P E C T I V E S

In this review we have presented examples illustratingan ancient principle of cellular communication found in

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vertebrates and eukaryots, e.g. from Drosophila and C.elegans to humans, even with rudimentary roots in bacteria.The common theme for the different types of hormones andmediators, is that they are shuttled between biologicallyactive and inactive forms by enzymes that belong to a fewdifferent superfamilies. Thus, the important physiologicalprinciple is that the hormonal action in a target cell isdetermined by enzyme action within the cell, not only bycirculating hormone levels and receptor expression. Theemerging question is why such a complex system betweendifferent ligands, enzymes and receptors has evolved?Local biotransformation of the ligand allows a givenreceptor to be utilized for different ligands in differentcells (e.g. MR in CNS and kidney, binding cortisol/aldosterone). It clearly is a way of evolution to introducespecificity while maintaining flexibility for adaptation toexternal signals and stressors, i.e. by combination of twoserial semispecific building blocks (enzymes, receptors)the system achieves higher specificity within a givencompartment through a filter effect.

Modification of nuclear receptor signalling pathways is acurrently pursued avenue in drug development, exemplifiedwith the development of PPAR a and g agonists [131,132].As outlined here, it is possible to find alternative drugtargets more `upstream' in the signalling pathway. Indeed, anumber of enzymes described in this review are already infocus in drug development (e.g. 3a-HSD or 17b-HSD inhormone-dependent cancer forms [133,134]), while othersare waiting to be explored [135].

All, or most, of the molecules described in this reviewhave long been recognized as signaling molecules, althoughthe signal transduction principles have been deduced later.A current research trend indicates the reverse: a signalingsystem with the key molecular component waiting tobecome identified, which is the case for some of the`orphan nuclear receptors' [4]. This search has lead to theidentification of signaling molecules separate from classicalhormones [136±139]. Furthermore, it is now widelyaccepted that important signaling molecules are derivedfrom major food constituents, such as polyunsaturated fattyacids [140±142]. Many enzymes and isoforms involved intransformation of these and other nonclassical signalingmolecules are waiting to be identified, and it would not besurprising if the principle of enzymatic modulation of localeffects will be extended into further areas of signalingmolecules.

A C K N O W L E D G E M E N T S

Critical reading of the manuscript and fruitful discussions with Jan

SjoÈvall, Jesper HaeggstroÈm and Anders Berkenstam, Stockholm are

gratefully acknowledged. Research in the authors' laboratories has

been supported by the European Commission (BIO4CT2123), Swedish

Union of Physicians, NovoNordisk Foundation, Loo och Hans Oster-

mann Foundation, Pharmacia Corporation, BioNetWorks GmbH,

Munich, Stockholm University, and Karolinska Institutet.

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