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Gut, 1991,32,408-412
Biotransformation enzymes in human intestine:critical low levels
in the colon?
W H M Peters, L Kock, F M Nagengast, P G Kremers
AbstractBiotransformation or drug-metabolisingenzymes have an
important function in thedetoxication of ingested toxic,
carcinogenic,or tumour promoting compounds. Enzymeactivity and
isoenzyme composition of threebiotransformation systems:
glutathione S-transferase, uridine
diphosphate-glucurono-syltransferase, and cytochrome P-450
werestudied in normal small and large intestinalmucosa from three
kidney donors. The activityof most drug-metabolising enzymes
decreasesslightly from proximal to distal small intestine,whereas
in the mucosa of the large intestine asharp fall in activity was
observed. The iso-enzyme composition for each of the
threebiotransformation systems changed from thesmall to the large
intestine. Class Alpha gluta-thione S-transferases were not
expressed in thecolon, in contrast to the small intestine whereboth
Alpha and Pi class isoenzymes arepresent. In addition, with
monoclonal anti-bodies fewer protein bands for
UDP-glucu-ronosyltransferases and cytochrome P-450were detected in
the colon. In the small intes-tine both isoforms P-4504 and P-450,
werepresent, whereas in the colon only reducedamounts of cytochrome
P-4504 could be visual-ised. For UDP-glucuronosyltransferase, 53and
54 kDa proteins could be detected in thesmall intestine, but in the
colon there was onlyweak staining ofthe 54 kDa band. In the
normalhuman colon enzymes are less active andthere are fewer
isoenzymes present in themucosa than in the small intestine.
Thisimplies a lower level of the detoxifying poten-tial in the
colon, which might be important inregard to the high rates
ofcarcinogenesis in thecolon.
Division ofGastrointestinal andLiver Diseases, StRadboud
Hospital,Nijmegen, TheNetherlandsW H M PetersL KockF M
Nagengast
Laboratoire de ChimieMedicale, Institut dePathologie, Universite
deLiege, BelgiumP G KremersCorrespondence to:Dr W H M Peters,
Division ofGastrointestinal and LiverDiseases, St RadboudHospital,
PO Box 9101, 6500HB Nijmegen, TheNetherlands.Accepted for
publication26 June 1990
Biotransformation is the sum of all chemicalreactions that alter
the nature, water solubility,and distribution of non-nutritive
compoundsthat are potentially toxic or carcinogenic. Suchcompounds
may enter the body as food com-ponents, food additives, or drugs.
The gastro-intestinal tract often is the route of entry ofsuch
harmful molecules and the gastrointestinalmucosa can be very active
in biotransformation.Data on human intestinal
biotransformationenzymes are, however, relatively scarce.'2
Thepresence of both phase IP- and phase II51"6biotransformation
enzymes has been shown.Compared with the liver, however, the
specificactivity of these enzymes in small intestinalmucosa may be
lower, apart from glutathioneS-transferase.'"From the small to the
large intestine the
activity of glutathione S-transferase seems to
1200
1000-
* 800-C
.c_° 600
0.-400
E
200
1800
1600
.E1400-'E.E 1200-0a 1000-
0)E~ 800~
E600.
400
200
0
350
300
X 2500
E 200
E150
100
50
0
GST
4-np UDPGT
IBilirubin UDPGT
1.
z,01~0J
1T
a- d IL
15>
Figure 1: Longitudinal distribution of
intestinalbiotransformation activities. Activities for
cytosolicglutathione S-transferase (GST) microsomal
4-nitrophenoluridine diphosphate-glucuronosyltransferase (UDPGT),
andbilirubin UDPGT were determined as indicated underMethods.
Enzyme assays were performed in mucosa obtainedfrom segments ofthe
proximal (duodenum), mid (jejunum),and distal (ileum) small
intestine. In addition, three colonicsegmentsfrom proximal
(caecum), mid (transverse colon),and distal (sigmoid colon) large
intestine were investigated.Activities were determined in
triplicatefor each subject andare given as means (SEM)for three
subjects. Small intestinalvalues arefrom four subjects since some
data from Peterset al' are included. nd=not detectable.
408
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Biotransformation enzymes in human intestine: Critical low
levels in the colon?
1 2 3 4 5 6:.1..I..: 1 3.. 4 5Figure 2: Sodium dodecyl
sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) ofpurified
intestinal glutathioneS-transferases. Glutathione-agarose purified
glutathione S-transferases were subjected to sodium dodecyl
sulphate-polyacrylamide gel electrophoresis (10% acrylamide, wlv)
and subsequently stained with Coomassie brilliant blue.
Purifiedintestinal glutathione S-transferases from patient 1 (5-10
ig protein) are shown in panel A, slots 1-6. Purified
transferasesfrom patient 2 (8-12 Rgprotein) are shown in panel A,
slots 7-12, and thosefrom patient 3 (3-10 Rg protein) are shown
inpanel B, slots 1-4. In panelB slot 5 purified hepatic glutathione
S-transferases (5 tg protein) from patient 3 were
applied.Preparations shown arefrom duodenum (A, I and 7; B, 1),
jejunum (A, 2 and 8), ileum (A, 3 and 9; B, 2), caecum (A, 4and 10;
B, 3), transverse colon (A, 5 and 11), and sigmoid colon (A, 6 and
12; B, 4). Glutathione S-transferase Pi subunitsare indicated by
arrow.
decrease."" The isoenzyme composition fromcytochromes P-45047 as
well as glutathioneS-transferases'4 may also be different in
largebowel mucosa. Most available data, however,come from analysing
separate specimens fromdifferent subjects. Therefore, the
possibility can-not be excluded that some of the differences aredue
solely to interindividual variations.We have investigated the
longitudinal distri-
bution and isoenzyme composition of phase I(cytochrome P-450)
and phase II drug-metabol-isilng enzymes (uridine
diphosphate-glucurono-syltransferases, glutathione S-transferases)
innormal small and large intestinal mucosa fromthree kidney donors.
Significant differences inisoenzyme composition and activity were
foundbetween the two parts of the intestine.
Methods
TISSUEHuman intestines were obtained from threekidney donors.
Donor 1 was a female aged 3-5
months, who died after a head injury (traumacapitis). Donor 2
was an 18 year old man whodied from cerebral damage after a
subdural/subarachnoid haemorrhage. Donor 3 was a 49year old man who
died after a head injury. Dataon small intestinal biotransformation
activitiesobtained from another male kidney donor (an 18year old5)
are also incorporated in Figures 1and 4. None of the donors had
gastrointestinaldisorders.
After removal, intestine was stored on iceduring transport to
the laboratory. The intestinewas opened and cleaned by repeated
washingswith ice cold 0-9% NaCl. Tissue was cut intosegments,
frozen in liquid nitrogen, and stored at-80°C until use.From
segments (length 20-40 cm; area 70-
200 cm2), taken at intervals of 60-120 cm,mucosa was isolated.
Mucosa was homogenisedand cytosolic" and microsomal fractions
weremade as described previously.41'The investigations were
approved by the
local ethical committee on human experimenta-tion.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 1516 1718 19 1. 2 3 4 5Figure
3: Immunodetection ofintestinal glutathione S-transferase-Pi. Human
intestinal cytosol (75 RLg protein) was subjectedto sodium dodecyl
sulphate-polyacrylamide gel electrophoresis and subsequent Western
blotting to nitrocellulose. GST-Pi wasimmunadetected with a
monoclonal antibody against GST-Pifrom human placenta.2 Cytosols
from proximal to distal smallintestine (panel A, slots 1-6, patient
1; A, 10-15, patient 2; B, 2 and 3, patient 3) andfrom proximal to
distal large intestine(A, 7-9, patient 1; A, 16-18, patient 2; B, 4
and 5, patient 3) are shown respectively. In panelA slot 19 and
panelB slot Ipurified glutathione S-transferase Pifrom human
placenta (0.5 ptg protein) was applied to the gels. The lowest band
visible inpanelB slot 2 may be an additional acidic glutathione
S-transferase-Pi isoform.
409
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Peters, Kock, Nagengast, Kremers
....... ......
Figure 4: Immunodetection of intestinal
UDP-glucuronosyltransferases. Intestinalmicrosomes from patients 2
and 3 were subjected to sodium dodecyl sulphate-polyacrylamidegel
electrophoresis (7% acrylamide; w/v) and subsequent Western
blotting. The blot wasincubated with a monoclonal antibody against
human UDP-glucuronosyltransferases. InpanelA small intestinal
microsomesfrom patient 2 (20 pg protein) originating at distances
of0, 100, 200, 340, 460, and 610 cmfrom the pylorus were applied in
slots 1-6, respectively. Inslots 7-9 large intestinal microsomes
(40 [g protein) from the caecum and transverse andsigmoid colon are
shown. Slot 10 contains 4 kg hepatic microsomesfrom another
patient. InpanelB microsomesfrom liver (15 ig protein), duodenum
(50 Rg), ileum (50 Rg), caecum (100Rg), and sigmoid colon (100
kg)from patient 3 are shown in the slots 1-5, respectively.
ENZYME DETERMINATIONSCystosolic glutathione S-transferase
activity with1-chloro 2,4-dinitrobenzene as substrate wasmeasured
by the method of Habig et al.`7 UDP-glucuronosyltransferase
activity with 4-nitro-phenol and bilirubin as substrates was
measuredin microsomes and whole homogenate, respec-tively, in the
presence of 0-0125% TritonX- 100. 18-20
MISCELLANEOUSGlutathione S-transferases were purified
asdescribed previously.'4 Protein was determinedby the method of
Lowry et al.2' Sodium dodecylsulphate-polyacrylamide gel
electrophoresis wasdone according to Laemmli.22 After staining
with
Coomassie brilliant blue, gels were scanned at600 nm with a
laser densitometer (LKB 2202Ultrascan, LKB, Bromma Sweden).
Immuno-blotting with monoclonal antibodies againstcytochrome
P-450,4 UDP-glucuronosyltrans-ferase,'3 and glutathione
S-transferases2'24 wasperformed as described previously.'6
ResultsThe intestines from the kidney donors weredivided in
segments of approximately 20 cm.Mucosa was isolated from segments
taken at theindicated locations (see figure legends). Mucosawas
homogenised and subcellular fractionsmade.
In the cytosolic fractions specific activity ofglutathione
S-transferase was determined (Fig1). Activities are highest in the
proximal smallintestine and show a sharp fall from small to
largeintestine.The longitudinal distribution of microsomal
UDP-glucuronosyltransferases with bilirubinand 4-nitrophenol as
substrates is also shown inFigure 1. In the small intestine
activity of4-nitrophenol UDP-glucuronosyltransferase ismore or less
constant, whereas the conjugation ofbilirubin is decreasing. In the
three subjectsinvestigated a dramatic fall in activity for
4-nitro-phenol as well as for bilirubin
UDP-glucu-ronosyltransferase in the large intestine
wasobserved.
Small and large intestinal glutathione S-trans-ferases were
purified by affinity chromatographyon glutathione-agarose. These
purified prepara-tions are shown in Figure 2. Glutathione
Stransferases from small intestine are composed ofboth class Alpha
(25 kDa subunits) and class Pi(24 kDa subunits) isoenzymes. In
purified gluta-thione S-transferase preparations from
colonicmucosa, after Coomassie brilliant blue stainingonly class Pi
transferases were present. With amonoclonal antibody developed
against gluta-thione S-transferase Pi from human placenta23
1 2 3 4 5 6 7 8 9 101112t 13 14 t 16 17 18 19 1 2 3 4
Figure 5: Immunodetection ofintestinal cytochromes P-45056.
Intestinal microsomesfrom patient 1 (panel A, slots 2-10),patient 2
(A, 11-19), and patient 3 (B, 1-4) were subjected to sodium dodecyl
sulphate-polyacrylamide gel electrophoresis (7%acrylamide, w/v) and
Western blotting and subsequently incubated with a monoclonal
antibody against cytochromes P450,,.Hepatic microsomes (8 Rg
protein) are seen in panelA slot 1, microsomesfrom proximal to
distal small intestine (30 pog protein)are in panel A, slots 2-7
and 11-16, panel B, slots 1 and 2. Microsomesfrom proximal to
distal large intestine (60 ptg protein)were applied in panel A,
slots 8-10 and 17-19, panel B, slots 3 and 4. In slot 13, for
unknown reasons, little protein hasmoved into the gel. The 54 kDa
band ofcytochrome P450J is indicated by arrow. Other cytochrome
P450 related proteinbands seen have molecular masses of52 kDa
(liver and intestine) and 56 kDa (liver).
410
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Biotransformation enzymes in human intestine: Critical low
levels in the colon?
.~~~~~~~~ ~ ~ ~ ~ ~ ~ ~~~~~~~~~~~~.3ta
Figure 6: Immunodetection of intestinal cytochrome P-450.
Intestinal microsomes from patient 1 (panel A, slots 1-9), patient2
(A, 10-18), and patient 3 (B, 2-5) were subjected to sodium dodecyl
sulphate-polyacrylamide gel electrophoresis (7%acrylamide, w/v) and
subsequent Western blotting. Cytochrome P.4505 was detected with a
monoclonal antibody. Hepaticmicrosomesfrom patient 3 (4 Rg protein)
are seen in panelB slot 1; microsomesfrom proximal to distal small
intestine (20 tgprotein) are seen in panel A, slots 1-6 and 10-15,
panel B, slots 2 and 3. Microsomes from proximal to distal large
intestine(40 [tg protein) were applied in panel A, slots 7-9 and
16-18, panel B, slots 4 and 5. The band representing cytochromeP450
has a molecular mass of52 kDa.
this isoenzyme was indeed readily shown incytosolic fractions
from both small and largeintestine (Fig 3).By immunodetection,
using a monoclonal
antibody against class Mu glutathione S-trans-ferases,24 small
amounts of this isoform weredetected in all intestinal segments
from twopatients (not shown). In the intestine frompatient 1 this
isoenzyme was absent. Hepaticglutathione S-transferases from
patient 3 are alsoshown in Figure 2. Here only class Alphaisoforms
and no class Pi subunits are present.On a Western blot, small
intestinal micro-
somes from patients 2 and 3, incubated with amonoclonal antibody
against UDP-glucuronosyltransferase, show two very closebands. In
the corresponding colonic micro-somes, even when twice as much
protein isapplied to the gel, only a very weak protein bandis
visible (Fig 4). Intestinal microsomes frompatient 1 gave only very
weak bands in the smallintestine and no staining at all in the
colon (notshown).A Western blot of small intestinal microsomes,
treated with a monoclonal antibody against cyto-chromes
P-4504,5,6, shows two bands of 52 and 54kDa (Fig 5). In the
proximal small intestine frompatient 1, the 54 kDa band is very
weak (Fig 5,panel A). In colonic microsomes the 52 kDa bandis not
detectable. Figure 6 shows that immuno-detection of cytochrome
P-4505 is possible onlyin small intestinal, but not in colonic,
micro-somes from all subjects. It should be noted thathere again
for the large intestinal samples twice asmuch protein was applied
to the gels.
DiscussionLongitudinal distribution of the biotransforma-tion
enzyme activities measured show a decline inactivity, with a sharp
fall from the small to thelarge intestine. For glutathione
S-transferases,such a large decrease in activity in colonic
mucosawas noted before in specimens obtained frompatients with
carcinoma of the colon and rec-tum'3 i4 and in rodents.225 The
intestines investi-gated here were from patients with no
intestinaldisease. Thus the relatively low colonic gluta-thione
S-transferase activities are not restricted
to patients with malignancies of the largebowel.23
Glutathione S-transferase subunit compositionis different in
small and large intestinal mucosa.The small intestine contains
class Alpha, Mu,and Pi isoenzymes, whereas in the colon
predomi-nantly class Pi subunits can be detected. ClassMu subunits
are present in very small amountsand c4n hardly be seen after
Coomassie brilliantblue staining of the sodium dodecyl sulphate
gelshown in Figure 2. Thus in contrast to otherreports2627 we found
class Pi subunits almostexclusively, both in normal and
neoplastic23colonic tissue. Our results confirm the
recentimmunohistochemical findings of Hayes et a128giving a similar
isoenzyme distribution in smalland large intestine.The presence of
bilirubin UDP-glucuronosyl-
transferase activity in the small intestines from allsubjects
investigated once again confirms thatbilirubin metabolism is not
restricted to theliver.5 12 29 30 Moreover, specific activities of
hepa-tic and small intestinal bilirubin
UDP-glucu-ronosyltransferase do not differ dramatically(mean (SEM)
704 (42) and 343 (22) nmol/gtissue/h, respectively; data are from
patient 3).Similar data obtained from another patient havebeen
reported before.'Immunoblot studies with an antibody against
UDP-glucuronosyltransferase show two closebands in the small
intestine, whereas in colonicmucosa both bands were hardly visible.
The twosmall intestinal bands (53 and 54 kDa) maycorrespond to
activities for bilirubin (53 kDa)and 4-nitrophenol (54 kDa).5 Both
activities aredrastically reduced in the colon, and here theamount
of UDP-glucuronosyltransferase proteinmay be below the detection
limit for immuno-blots.For isoenzymes of the cytochrome P-450
bio-
transformation system a similar case exists.Isoform P-450, is
detectable in the small intestinebut not in the colon. Another
isoenzyme, pro-bably P-4504, is present in both colonic and
smallintestinal mucosa. Since more large intestinalmiciosomes were
loaded onto the gel it may beconcluded from the immunoblot in
Figure 5 thatthe levels of P-4504 in the colon of all patients
arelower compared with those in the small intestine.
41
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412 Peters, Kock, Nagengast, Kremers
The above experimental data on biotransfor-mation enzyme
activities in the intestines ofhealthy kidney donors show a
constant ordecreasing activity along the small intestine and
asignificant fall in activity in the colon. For allthree enzyme
systems investigated here thenumber of isoenzymes in the colon is
reduced.This pattern of both reduced enzyme activitiesand isoenzyme
composition undoubtedly willresult in a lower level ofdetoxication
in the colon.Activities of biotransformation enzymes in thecolon
may further decrease with increasingage.'4 3' In addition, levels
of j3-glucuronidase arehighest in the colon.32 This could result in
lesstoxic glucuronides becoming toxic again bydeconjugation.
Indeed, high concentrations ofmutagens have been detected in the
humancolon.33 In conclusion, the detoxicating capacityin the human
colon could be at a critical low levelwhich may contribute to the
high rate of coloniccancer.
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Effects of semisynthetic diets on xenobioticmetabolizing enzyme
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4 Peters WHM, Kremers PG. Cytochromes P-450 in the intes-tinal
mucosa of man. Biochem Pharmacol 1989; 38: 1535-8.
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6 Watkins PB, Wrighton SA, Schuetz EG, Molowa DT,Guzelian PS.
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