The carcinogenic antioxidants,N-phenyl-1-naphthylamine (P1NA)and N-phenyl-2-naphthylamine (P2NA) were examined in vitro for biotransformation by rat hepatic microsomes and in freshly isolated hepatocytes. HPLC-analysi...The carcinogenic antioxidants,N-phenyl-1-naphthylamine (P1NA)and N-phenyl-2-naphthylamine (P2NA) were examined in vitro for biotransformation by rat hepatic microsomes and in freshly isolated hepatocytes. HPLC-analysis of hepatocyte incubations with revealed that phenols were the major metabolites in both cases. P1NA formed one phenolic metabolite only, while incubation with P2NA yielded two phenols identified as 6-hydroxy-P2NA and 4’-hydroxy-P2NA by cochromatography with authentic samples. β-naphthylamine, a metabolite indicating dephenylation of P2NA was not detectable.Metabolism studies with microsomes revealed that the phenols were formed by cytochrome P-450 dependent monooxygenases. Pretreatment of animals with phenobarbital and 3-methylcholanthrene both increased the rate of microsomal metabolism of P1NA and P2NA, indicating that more than one P-450 enzyme mediate the oxygenation reaction. Animal pretreatment with single and repeated doses of P1NA and P2NA did not markedly stimulate metabolism,展开更多
2-naphthylamine was incubated with induced rat liver microsome S9 preparation and the metabolites were separated through HPLC. The following products were identified: 2-amino-5-naphthol, 2-amino-6-naphthol, 2-amino-7-...2-naphthylamine was incubated with induced rat liver microsome S9 preparation and the metabolites were separated through HPLC. The following products were identified: 2-amino-5-naphthol, 2-amino-6-naphthol, 2-amino-7-naphthol and 2-amino-8-naphthol. The yields of these four metabolites are varying in quantity, and the relative contents of 2-amino-8-, -5-, -6- and -7-naphthol are 52.6%, 28.5%, 14.0% and 4.9% respectively. These results are consistent with the quantitative HMO calculation and inference based upon Di-region theory, i.e., the metabolisms of aryl amines on extra-ring (assigned the ring without the substituent of amino group) are through the epoxidation and then NIH shift, but are not the direct hydroxylation in the formation of phenols. It is shown that both the amino group and the carbon atoms on the extra-ring play duality roles of activation and detoxification in metabolism.展开更多
文摘The carcinogenic antioxidants,N-phenyl-1-naphthylamine (P1NA)and N-phenyl-2-naphthylamine (P2NA) were examined in vitro for biotransformation by rat hepatic microsomes and in freshly isolated hepatocytes. HPLC-analysis of hepatocyte incubations with revealed that phenols were the major metabolites in both cases. P1NA formed one phenolic metabolite only, while incubation with P2NA yielded two phenols identified as 6-hydroxy-P2NA and 4’-hydroxy-P2NA by cochromatography with authentic samples. β-naphthylamine, a metabolite indicating dephenylation of P2NA was not detectable.Metabolism studies with microsomes revealed that the phenols were formed by cytochrome P-450 dependent monooxygenases. Pretreatment of animals with phenobarbital and 3-methylcholanthrene both increased the rate of microsomal metabolism of P1NA and P2NA, indicating that more than one P-450 enzyme mediate the oxygenation reaction. Animal pretreatment with single and repeated doses of P1NA and P2NA did not markedly stimulate metabolism,
文摘2-naphthylamine was incubated with induced rat liver microsome S9 preparation and the metabolites were separated through HPLC. The following products were identified: 2-amino-5-naphthol, 2-amino-6-naphthol, 2-amino-7-naphthol and 2-amino-8-naphthol. The yields of these four metabolites are varying in quantity, and the relative contents of 2-amino-8-, -5-, -6- and -7-naphthol are 52.6%, 28.5%, 14.0% and 4.9% respectively. These results are consistent with the quantitative HMO calculation and inference based upon Di-region theory, i.e., the metabolisms of aryl amines on extra-ring (assigned the ring without the substituent of amino group) are through the epoxidation and then NIH shift, but are not the direct hydroxylation in the formation of phenols. It is shown that both the amino group and the carbon atoms on the extra-ring play duality roles of activation and detoxification in metabolism.
