A comparison of the ontogeny of enterocytic and hepatic cytochromes P450 3A in the rat

Enzymes of the cytochrome P450 3A (CYF3A) sub-family are abundant in adult liver and gut and contribute significantly to the first-pass metabolism of many orally administered drugs. The development of CYP3A enzymes with regar d to their expression and activity in enterocytic and hepatic microsomes fr om 1-day-old through to adult male and female rats has been studied. Micros omes were prepared by calcium precipitation. Enzyme expression was assessed semi-quantitatively by Western blotting using rat polyclonal CYP3A2 and 2C 11 antibodies and peptide antibodies specific to rat CYPs 3A1, 3A2, 2C12, a nd 2C13, The formation of 6 beta -hydroxytestosterone (6OHT), determined by HPLC, was used as a measure of enzyme activity. Formation of 6OHT by enter ocytic microsomes was similar for males and females and showed a sharp incr ease at weaning. This pattern was mirrored by levels of immunoquantifiable CYP3A2 (CYP3A9), but CYP3A1 followed a more gradual development. CYPs 2C11, 2C12, or 2C13 were not detected in gut microsomes. In contrast, CYPs 3A1, 3A2, 2C11, 2C12, and 2C13 were all expressed in hepatic microsomes. There w as no surge in hepatic enzyme expression or hepatic 6OHT formation at weani ng, and a marked sex difference in 6OHT formation was apparent from day 25. The surge in gut activity at weaning may be a protective mechanism against ingested toxins. (C) 2000 Elsevier Science Inc.