CHARACTERIZATION OF CYP3A GENE SUBFAMILY EXPRESSION IN HUMAN GASTROINTESTINAL TISSUES

The human CYP3A subfamily is of interest due to its multiplicity, acti vity toward known carcinogens, and extrahepatic expression. In situ hy bridisation analysis of formalin fixed, routinely processed biopsy spe cimens was used to localise CYP3A mRNA in human gastrointestinal tissu es from several individuals. CYP3A mRNA is abundant in human liver and in mucosal epithelial cells of all segments of the human small intest ine. RNA blot analyses showed that the mRNA species observed in most l ivers and in human small intestine represent CYP3A3/3A4 transcripts. T his was confirmed at the protein level by immunoblot comparison of sma ll intestine microsomes to in vitro expressed CYP3A4 and CYP3A5 protei ns. In liver and small intestine, CYP3A mRNA is not uniformly distribu ted, with grain density highest in cells within the respective non-pro liferative compartments. CYP3A mRNA was also observed in human oesopha gus and colon. RNA blot analysis of multiple colons showed heterogenei ty 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 CY P3A5 to activate the dietary heterocyclic amine MeIQ in the presence o f alpha-naphthoflavone was shown. These results show that there is con siderable heterogeneity in the expression of the CYP3A subfamily in hu man gastrointestinal tissues.