Genetic and developmental diversity of hepatic cytochromes P450. Warfarin and progesterone metabolism by hepatic microsomes from four inbred strains of rat.

Hepatic microsomes from immature and sexually mature male and female ACI/SEGHsd, F344/NHsd, SHR/NHsd, and WKY/NCrl inbred rats were used to study cytochrome P450 (P450)-catalyzed oxidations of progesterone and both enantiomers of warfarin. Strains were selected on the basis of their different, homozygous allelic compositions for CYP2C11 and CYP2C13 (Rampersaud and Walz, 1992), but no correlations with the microsomal activities were observed. However, correlations were made regarding catalytic activities and the developmental control of CYP2A1 and CYP2C11 levels in microsomes. Other correlations were found for reactions of both warfarin enantiomers at the same atom or for a given enantiomer at different positions, and these appear to involve several P450 isozymes. Strain-dependent activity differences mainly involved the SHR/NHsd and WKY/NCrl strains. WKY/NCrl rats were the most unique strain, having low levels of CYP2C11 in adult males compared with the other inbreds but relatively high S-warfarin 4'- and 6-hydroxylase activities in immature animals of both sexes and adult females. These results suggest that the regulation and/or allozymic composition of hepatic P450s are different for WKY/NCrl rats, which makes them a poor choice as "normotensive controls" in comparison with hypertensive SHR rats.