EFFECTS OF RP-52028 AND PHENOBARBITAL ON MESSENGER-RNA LEVELS OF INDUCIBLE AND CONSTITUTIVE SEX-SPECIFIC CYTOCHROME-P450 ISOZYMES IN RAT-LIVER

Sex-related differences in basal levels of mRNA coding for various cytochrome P450 isozymes and their inducibility by 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (RP 52028) in comparison to phenobarbital (PB) were investigated in Sprague-Dawley rats. We observed that the inducible isozymes, namely cytochromes P450IIB1/2 and P450IIIA1/2 were barely detectable in non-induced animal livers. On the contrary, mRNAs coding for two constitutive forms of cytochrome, P450IIC7 and IIC11, were expressed at a high level in untreated rats in a sex-dependent manner. Cytochrome P450IIC11 mRNA was present in male rats only whereas P450IIC7 was expressed in both sexes but at a higher level in female rats. RP 52028 had a dose-dependent inducing effect on the P450IIB1/2 and IIIA1/2 isoforms in both sexes. After administration of a high dose (500 mg/kg), this molecule exhibited a pattern of induction similar to that of PB. Increases in the accumulation of these IIB1/2 and IIIA1/2 messengers were correlated with protein data, suggesting that RP 52028, like PB, induces these isozymes mainly through a pretranslational regulatory mechanism. On the other hand, PB and RP 52028 caused only a slight increase, less pronounced than in Wistar rats, in the mRNA level of the constitutive female-predominant P450IIC7, indicating a strain-related difference in inducibility of this isozyme. RP 52028 had no effect on P450IIC11 mRNA level in male rat liver, in contrast to the decreasing effect obtained with PB. Furthermore, the non-correlated changes in P450IIC11 mRNA level and microsomal testosterone 2-alpha-hydroxylase activity after treatment with RP suggests that this molecule modulates the expression of P450IIC11 at a posttranscriptional level only.