INDUCTION OF THE MALE-SPECIFIC CYTOCHROME-P450 3A2 IN FEMALE RATS BY PHENYTOIN

We previously reported that administration of dexamethasone (DEX) and other selected pharmacological agents to rats resulted in a profound i ncrease in hepatic cytochrome P450 3A2 in both sexes, but male constit utive P450 3A2 was modestly increased (4-fold) in adult males and not detected in either treated or untreated females (Cooper ct at., Arch. Biochem. Biophys. 301, 345, 1993). Using a more sensitive Western blot stain, we have now detected in females low but significant induction of P450 3A2 by DEX. Of 10 compounds tested, DEX was the most effective inducer of P450 3A1 in either sex and of P450 3A2 in males. Unexpecte dly, the antiepileptic, phenytoin, was the most potent inducer of P450 3A2 in females, resulting in levels up to 30% of those seen in untrea ted males. Even more striking, phenytoin differentially induces the ma le-specific P450 3A2 with barely detectable increases in P450 3A1 in e ither sex. By comparison, when administered to female rats, the other active P450 3A inducers preferentially induce P450 3A1 compared to 3A2 by ratios ranging from 3- to 400-fold, Another male-specific isozyme, P450 2C11, was induced in females by both DEX and phenytoin, but DEX was much more effective than phenytoin. These results suggest that the masculinization of expression of these two sexually dimorphic isozyme s of cytochrome P450 may occur by different mechanisms, and that pheny toin is atypical of the other nine compounds we tested. Moreover, of t he known inducers of the ''steroid inducible'' 3A family, phenytoin is unique in its ability to differentially induce P450 3A2 compared to P 450 3A1, particularly in the female rat. Also, administration of pheny toin to female rats gave rise to P450 3A2 levels that could be divided into two distinct classes of high and low levels of P450 3A2. Should this prove to be a genetic polymorphism it could be very useful in stu dies on the mechanism of P450 3A2 induction. (C) 1996 Academic Press, Inc.