Induction of the cytochrome P450 I and IV families and peroxisomal proliferation in the liver of rats treated with benoxaprofen. Possible implications in its hepatotoxicity.
Administration of the non-steroidal anti-inflammatory drug benoxaprofen to rats gave rise to significant increases in the hepatic O-dealkylations of ethoxyresorufin and methoxyresorufin and in the 12-hydroxylation of lauric acid but, in contrast, the N-demethylation of dimethylnitrosamine was inhibited. Immunoblot studies employing solubilized microsomes from benoxaprofen-treated rats revealed that benoxaprofen increased the apoprotein levels of P450 IA1 and A2 and of P450 IVA1. The same treatment with benoxaprofen increased the beta-oxidation of palmitoyl CoA determined in liver homogenates, and immunoblot analysis showed an increase in the apoprotein levels of the trans-2-enoyl CoA hydratase bifunctional protein. It is concluded that benoxaprofen is a peroxisomal proliferator which selectively induces the hepatic cytochrome P450 I and IV families. The possible implications of these findings to the well-known hepatotoxicity of this drug are discussed.
Ayrton
A D
AD
Division of Toxicology, School of Biological Sciences, University of Surry, Guildford, U.K.
Ioannides
C
C
Parke
D V
DV
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000633:toxicity; D002994:Clofibrate / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004746:Enoyl-CoA Hydratase / Q000378:metabolism; D004790:Enzyme Induction; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000201:enzymology; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011422:Propionates; D010171:Palmitoyl Coenzyme A; C011677:benoxaprofen; D003577:Cytochrome P-450 Enzyme System; D004746:Enoyl-CoA Hydratase; D002994:Clofibrate