Modulation of rat hepatic cytochromes P450 by chronic methapyrilene treatment.
The antihistaminic compound methapyrilene (MP) when chronically administered has been shown to be a rat-specific hepatocarcinogen. To examine the effects of chronic MP treatment on the hepatic microsomal cytochromes P450. Fischer 344 rats were gavaged for 10 weeks (5 days on, 2 days off) with either vehicle or 50, 100, or 150 mg MP/kg body weight. Chronic MP treatment was found to have a significant effect on several microsomal enzymatic activities. Small (17-28%) but significant (P less than 0.05) decreases were observed for total P450 levels and the activities of erythromycin N-demethylase (catalyzed by P450IIIA), N-nitrosodimethylamine demethylase (catalyzed by P450IIE1) and pentoxyresorufin O-dealkylase (catalyzed by P450IIB1). In addition, a relatively large decrease (approximately 80%) was observed for the activity of benzphetamine N-demethylase (representative of P450IIC11) and an induction of about 40% was observed for ethoxyresorufin O-dealkylase (catalyzed by P450IA). The metabolism of testosterone by microsomes isolated from the rats chronically treated with MP indicated that several reactions were compromized. Specifically, testosterone 2 alpha-hydroxylase, indicative of P450IIC11, was reduced greatly (86%), whereas testosterone 6 beta-hydroxylase, reflecting P450IIIA, and testosterone 7 alpha-hydroxylase, indicative of P450IIIA1, were affected only slightly by MP treatment (approximately 25%). Immunoblot analyses of the various microsomal samples were performed to determine if chronic MP treatment had direct effects on the level of expression of the cytochromes P450. Decreases in the levels of P450IIIA, IIE1, and IIC11, determined by immunoblot analyses, closely paralleled those observed for their marker catalytic activities. Further studies will be required to determine the mechanism by which MP affects the levels of the cytochromes P450 (i.e. increased degradation or decreased synthesis).
Wrighton
S A
SA
Department of Drug Metabolism and Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
VandenBranden
M
M
Brown
T J
TJ
Van Pelt
C S
CS
Thomas
P E
PE
Shipley
L A
LA
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008701:Methapyrilene / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013739:Testosterone / Q000378:metabolism
D007527:Isoenzymes; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D008701:Methapyrilene