Effects of xylene exposure on the metabolism of antipyrine in vitro and in vivo in the rat.
Exposure of male rats to different concentrations of xylene for 3 days induced, in a dose-dependent way, the in vitro liver microsomal metabolism of antipyrine. The degree of induction was statistically significant at an exposure level of 250 ppm and maximal (2.5-fold increase) at 2000 ppm. This increase was of the same magnitude as after phenobarbital treatment. Female rats had a lower basal antipyrine metabolism than males, but exhibited a greater relative increase in antipyrine metabolism following xylene exposure. Cytochrome P-450 isozymes, purified from xylene- and phenobarbital-treated animals, were efficient catalysts of antipyrine metabolism, with turnover numbers of 33.3 and 21.1, respectively. A reduction in the half-life of antipyrine to 39% of preexposure values occurred after exposure of male rats to 1000 ppm of xylene for 3 days. Exposure to lower xylene levels did not produce significant alterations in antipyrine elimination half-life. In vitro, xylene was shown to be a non-competitive metabolic inhibitor of antipyrine. Experiments in vivo indicated that inhibition is not important at relatively low xylene exposure levels. It is concluded that induction of hepatic monooxygenases by xylene can be demonstrated, with antipyrine as a test drug, both in vitro and in vivo.
D000818:Animals; D000983:Antipyrine / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010088:Oxidoreductases / Q000032:analysis; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D014992:Xylenes / Q000494:pharmacology*
D014992:Xylenes; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D000983:Antipyrine; D010634:Phenobarbital