Stereochemical selectivity in the induction of cytochrome P450IVA1 (P452)-dependent fatty acid hydroxylation and peroxisome proliferation

Abstract

Induction of hepatic microsomal cytochrome P450IVA1 and peroxisomal enzymes of the β-oxidation spiral were observed when male Long Evans hooded rats were administered optically pure enantiomeric forms and a racemic mixture of a clofibrate analogue [2-[4-(4-chlorophenyl)benzyloxy]-2-phenylacetic acid] at a dose level of 80 mg/kg for 3 days. The R(−)-enantiomer was found to be a more potent inducer of microsomal cytochrome P450IVA1 and its associated lauric acid 12-hydroxylase activity than its corresponding S(+)-antipode. This difference in potency was reflected by a eudismic ratio ( R/ S activity ratio) of approximately 3, whereas the racemic mixture exhibited a potency intermediary between the two isomers. An identical enantiomeric selectivity was observed for the phenomenon of peroxisome proliferation as judged by induction of cyanide-insensitive palmitoyl CoA oxidation and the bifunctional protein of the peroxisomal β-oxidation spiral. The highest potency was shown by the R(−)-isomer resulting in approximately a 3–6-fold increase over the control value. These increases were paralleled by an increase in total carnitine acetyl transferase activity with a eudismic ratio of approximately 4. In addition, immunochemical detection by Western blotting analysis for both the microsomal cytochrome P450IVA1 isozyme and the peroxisomal bifunctional protein was in agreement with the above modulation of catalytic activities. These results are therefore not inconsistent with the hypothesis that cytochrome P450IVA1 induction and peroxisome proliferation are intimately linked. Whether the observed stereochemical selectivity resides in xenobiotic recognition or disposition still remains to be determined.