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  • Title: Demethylation and denitrosation of nitrosamines by cytochrome P-450 isozymes.
    Author: Tu YY, Yang CS.
    Journal: Arch Biochem Biophys; 1985 Oct; 242(1):32-40. PubMed ID: 4051505.
    Abstract:
    Metabolism of nitrosamines was studied in a reconstituted monooxygenase system composed of cytochrome P-450 isozymes purified from liver microsomes of ethanol- and phenobarbital-treated rats. The ethanol-induced isozyme (P-450et) was efficient in catalyzing the demethylation of N-nitrosodimethylamine (NDMA), with a Km of 2.4 mM and Vmax of 7.2 nmol min-1 nmol P-450(-1), but less active with N-nitrosomethylbenzylamine and N-nitrosomethylaniline. The phenobarbital-induced form (P-450b) was ineffective in NDMA metabolism but was active in catalyzing the demethylation of N-nitrosomethylaniline, with an estimated Km of 0.08 mM and a Vmax of 7.2 nmol min-1 nmol-1. P-450et also catalyzed the denitrosation of NDMA with a Km of 13.6 mM and a Vmax of 1.36 nmol min-1 nmol-1. With control liver microsomes, multiple Km values were observed for the demethylation and denitrosation of NDMA. Involvement of superoxide radicals in the metabolism of NDMA was suggested by the action of superoxide dismutase, which inhibited the denitrosation by 43 to 73% and the demethylation by 13 to 22% in different monooxygenase systems. The P-450et-dependent NDMA demethylation was strongly inhibited by 2-phenylethylamine and 3-amino-1,2,4-triazole; these compounds were previously believed not to be inhibitors of P-450-dependent reactions but were found to inhibit microsomal NDMA demethylase. The present results establish the role of P-450 in nitrosamine metabolism and help to clarify some of the previous confusion in this area of research.
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