CYP3A GENE-EXPRESSION IN HUMAN GUT EPITHELIUM

CYP3A4, a major Phase I xenobiotic metabolizing enzyme present in live r, is also present in human small bowel epithelium where it appears to catalyse significant 'first pass' metabolism of some drugs. To determ ine whether CYP3A4 or the related enzymes CYP3A3, CYP3A5, and CYP3A7 a re present in other regions of the digestive tract, we used CYP3A-spec ific antibodies to examine histological sections and epithelial micros omes obtained from a human organ donor. CYP3A-related proteins were de tected in epithelia throughout the digestive tract and in gastric pari etal cells, in pericentral hepatocytes, and in ductular cells of the p ancreas. Immunoblot analysis suggested that the major CYP3A protein pr esent in liver, jejunum, colon, and pancreas was CYP3A4 or CYP3A3, whe reas CYP3A5 was the major protein present in stomach. Both CYP3A4 and CYP3A5 mRNA were detectable in all regions of the digestive tract usin g the polymerase chain reaction (PCR); however, only CYP3A4 could be d etected by Northern blot analysis. CYP3A7 mRNA was consistently detect ed only in the liver by PCR and CYP3A3 mRNA was not detected in any of the tissues. We conclude that CYP3A4 and CYP3A5 are present throughou t the human digestive tract and that differences in the expression of these enzymes may account for inter-organ differences in the metabolis m of CYP3A substrates.