Effects of induction and inhibition of cytochromes P450 on the hepatotoxicity of methapyrilene

The mechanisms by which the antihistamine drug methapyrilene causes acute p eriportal hepatotoxicity in rats are not yet elucidated. This study investi gated the effects of modulators of cytochrome P450 (CYP) activity on the he patotoxicity of methapyrilene and also the effect of methapyrilene on hepat ic CYP. Pretreatment of male Han Wistar rats with beta-naphthoflavone, phen obarbitone, butylated hydroxytoluene, piperonyl butoxide, Aroclor 1254, or cobalt protoporphyrin IX, agents known to modify hepatic CYP, all afforded some degree of protection against a hepatotoxic dose of methapyrilene (150 mg/kg x 3 days p.o.), as assessed by clinical chemistry and histology, Tota l hepatic CYP depletion by cobalt protoporphyrin IX treatment indicated CYP -mediated bioactivation was a prerequisite for methapyrilene-induced hepato toxicity, Protection against hepatic damage was strongly associated with be ta-naphthoflavone induction of CYP1A and phenobarbitone-associated CYP2B in duction. However, the role of CYP3A, which is constitutively expressed in t he liver and induced by piperonyl butoxide, butylated hydroxytoluene, or Ar oclor 1254, was unclear. Modulation of FAD monooxgenase activity by methima zole pretreatment was not associated with increased methapyrilene-induced h epatotoxicity, Methapyrilene treatment alone specifically decreased microso mal enzyme activity markers for CYP2C11, CYP3A, and CYP2A and pretreatment with all the hepatic enzyme-inducing agents specifically prevented the loss of CYP2C11. Together this suggested that CYP2C11 was responsible for the s uicide substrate bioactivation of methapyrilene and the toxicologic outcome largely relied upon an abundance of detoxifying enzymes present in the liv er. (C) 1998 Society of Toxicology.