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 increase in hepatic cytochrome P450 3A1 in both sexes, but male constitutive P450 3A2 was modestly increased (4-fold) in adult males and not detected in either treated or untreated females (Cooper et al., 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. Unexpectedly, the antiepileptic, phenytoin, was the most potent inducer of P450 3A2 in females, resulting in levels up to 30% of those seen in untreated males. Even more striking, phenytoin differentially induces the male-specific P450 3A2 with barely detectable increases in P450 3A1 in either 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 isozymes of cytochrome P450 may occur by different mechanisms, and that phenytoin is atypical of the other nine compounds we tested. Moreover, of the known inducers of the "steroid inducible" 3A family, phenytoin is unique in its ability to differentially induce P450 3A2 compared to P450 3A1, particularly in the female rat. Also, administration of phenytoin 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 studies on the mechanism of P450 3A2 induction.
Ghosal
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Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08855, USA.
Sadrieh
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N
Reik
L
L
Levin
W
W
Thomas
P E
PE
D000818:Animals; D000911:Antibodies, Monoclonal; D000927:Anticonvulsants / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000032:analysis; D010672:Phenytoin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D013739:Testosterone / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000927:Anticonvulsants; D005938:Glucocorticoids; D012333:RNA, Messenger; D013739:Testosterone; D010672:Phenytoin; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D039181:Steroid 16-alpha-Hydroxylase; C022657:steroid hormone 6-beta-hydroxylase