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Effects of methapyrilene hydro chloride on hepato carcinogenicity and pento barbital induced sleeping time in rats and mice



Effects of methapyrilene hydro chloride on hepato carcinogenicity and pento barbital induced sleeping time in rats and mice



Toxicology & Applied Pharmacology 66(2): 252-258



In a 6-8-mo. dose-response toxicity study, methapyrilene hydrochloride (HCl) was administered in the feed to Fischer-344/N rats and B6C3F1 mice at concentrations of 125, 250, 500, 1000, or 2000 ppm. After 26 wk, rats fed the higher dose levels of methapyrilene HCl developed cholangiocellular carcinomas in addition to severe hepatotoxic lesions. After 31 wk, mice exhibited only mild hepatotoxicity from ingesting methapyrilene HCl, even at the higher dose levels. The duration of sodium pentobarbital-induced sleeping time (PEN-induced ST) is determined by the rate of hepatic metabolism of PEN and can therefore be used as an in vivo measurement of the level of hepatic detoxifying enzymes. A subsequent study was undertaken with PEN-induced ST to investigate differences in the effect of methapyrilene HCl on hepatic detoxifying enzymes between the 2 species; in this study, prior treatment with methapyrilene HCl significantly increased PEN-induced ST of rats but not of mice, indicating that methapyrilene HCl had a suppressive effect on detoxifying enzymes in rats but not in mice. In other groups in this study, phenobarbital, a known inducer of hepatic detoxification enzymes, was administered simultaneously with methapyrilene HCl to both rats and mice. Methapyrilene HCl plus phenobarbital exerted a synergistic effect of enzyme induction in mice. In rats, the phenobarbital-induced hepatic enzymes increased the rate of hepatic detoxification of methapyrifene HCl, as measured by a reduction of PEN-induced ST as compared with that in control rats or rats receiving methapyrilene HCl alone. The difference in the effects of methapyrilene HCl on hepatic detoxifying mechanisms of rats and mice, as indicated by the metabolism of PEN, may explain the difference between the 2 species in their susceptibility to the hepatocarcinogenic effects of methapyrilene HCl.

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