Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues.
The human CYP3A subfamily is of interest due to its multiplicity, activity toward known carcinogens, and extrahepatic expression. In situ hybridisation analysis of formalin fixed, routinely processed biopsy specimens was used to localise CYP3A mRNA in human gastrointestinal tissues from several individuals. CYP3A mRNA is abundant in human liver and in mucosal epithelial cells of all segments of the human small intestine. RNA blot analyses showed that the mRNA species observed in most livers and in human small intestine represent CYP3A3/3A4 transcripts. This was confirmed at the protein level by immunoblot comparison of small intestine microsomes to in vitro expressed CYP3A4 and CYP3A5 proteins. In liver and small intestine, CYP3A mRNA is not uniformly distributed, with grain density highest in cells within the respective non-proliferative compartments. CYP3A mRNA was also observed in human oesophagus and colon. RNA blot analysis of multiple colons showed heterogeneity in the CYP3A mRNAs present. Two CYP3A mRNAs (CYP3A3/3A4 and CYP3A5) were detected in colon samples from several individuals. In addition to those localisation studies, the capacity of expressed CYP3A4 and CYP3A5 to activate the dietary heterocyclic amine MeIQ in the presence of alpha-naphthoflavone was shown. These results show that there is considerable heterogeneity in the expression of the CYP3A subfamily in human gastrointestinal tissues.
McKinnon
R A
RA
Department of Clinical Pharmacology, Flinders University, Bedford Park, South Australia.
Burgess
W M
WM
Hall
P M
PM
Roberts-Thomson
S J
SJ
Gonzalez
F J
FJ
McManus
M E
ME
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003106:Colon / Q000201:enzymology; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004064:Digestive System / Q000201:enzymology*; D004947:Esophagus / Q000201:enzymology; D005260:Female; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis
D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human