Human small intestine epithelial cells (enterocytes) provide the first site for cytochrome P450 (CYP)-catalyzed metabolism of orally ingested xenobiotics. CYP3A4 is the major form of CYP expressed in enterocytes and CYP2C is also expressed at a significant level. In this study, we further characterized the expression of CYP3A4 and CYP2C in human enterocytes and their interindividual variations by examining the metabolic activities from 10 individuals. CYP3A4 in human jejunum microsomes, as determined by 6β-testosterone hydroxylase activity, varied from 0.36 to 2.46 nmol/min/mg. The apparent average Km and Vmax values from two representative individuals were 54 μM and 3.2 nmol/min/mg, respectively. CYP2C9 and CYP2C19 in human jejunum microsomes, as determined by diclofenac 4′-hydroxylase and mephenytoin 4′-hydroxylase activities, varied over an 18-fold range (7.3-129 pmol/min/mg) and 17-fold range (0.8-13.1 pmol/min/mg), respectively. The mean apparent Km for diclofenac 4′-hydroxylase was 9.9 μM, whereas the apparent mean Km for S-mephenytoin 4′-hydroxylase was 79.3 μM. The mean intrinsic clearance (Vmax/Km) was approximately 130-fold greater for diclofenac 4′-hydroxylase than for mephenytoin 4′-hydroxylase. The metabolic activities of CYP2C9 and CYP2C19 were confirmed by inhibition by sulfaphenazole for CYP2C9 and ticlopidine for CYP2C19. In addition, CYP2C9 activities did not correlate with CYP3A4 activities, while CYP2C19 activities had a significant but poor correlation with those of CYP3A4. Thus the major CYP activities in human enterocytes have large interindividual variabilities that are not strongly related.
|Number of pages
|Drug Metabolism and Disposition
|Published - 2001
ASJC Scopus subject areas
- Pharmaceutical Science