Xylene induces a cytochrome P-450 isozyme in rat liver similar to the major isozyme induced by phenobarbital.
Rats pretreated with xylene or phenobarbital, and then exposed to n-hexane, exhibited a markedly increased peak serum concentration of the neurotoxic metabolite 2,5-hexanedione. In order to elucidate the mechanism underlying this synergistic effect, the major liver microsomal cytochrome P-450 isozymes induced by xylene and phenobarbital, respectively, were purified. In a reconstituted system both isozymes showed a high enzymatic activity with n-hexane as the substrate. Turnover numbers for the formation of 2-hexanol were 24 and 27 for the xylene- and phenobarbital-induced isozyme, respectively. The turnover numbers for 7-ethoxycoumarin, benzo[a]pyrene, and 1,1,2,2-tetrachloroethane were also in the same range for the two cytochrome P-450 preparations. The isozyme induced by xylene had an amino acid composition very similar to that of the phenobarbital-induced isozyme, and the purified proteins had identical electrophoretic mobilities on polyacrylamide gels in the presence of sodium dodecyl sulfate. Furthermore, similar peptide maps were obtained following digestion with alpha-chymotrypsin and papain, and each isozyme yielded a single immunoprecipitin band upon reaction with the immunoglobulin G fraction from rabbits immunized with the phenobarbital-induced enzyme. We conclude that xylene induces a rat liver microsomal cytochrome P-450 isozyme very similar to the major isozyme induced by phenobarbital and that this induction is the probable explanation for the enhanced formation of 2,5-hexanedione from n-hexane in vivo.
D000596:Amino Acids / Q000032:analysis; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006586:Hexanes / Q000494:pharmacology; D006588:Hexanones / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D013379:Substrate Specificity; D014992:Xylenes / Q000494:pharmacology*
D000596:Amino Acids; D006586:Hexanes; D006588:Hexanones; D007527:Isoenzymes; D014992:Xylenes; C026385:n-hexane; D003577:Cytochrome P-450 Enzyme System; C011269:2,5-hexanedione; D010634:Phenobarbital