Nature of N-nitrosodimethylamine demethylase in hepatic microsomes of rats.
The nature of enzymes involved in demethylation of N-nitrosodimethylamine (NDMA) was investigated in hepatic microsomes of rats. Compared to the other cytochrome P-450-dependent enzymes. NDMA demethylase had anomalous properties as reported in the literature. However, kinetic analysis suggested a qualitative change in NDMA demethylase induced by phenobarbital (PB) and 3-methylcholanthrene (MC) pretreatment. The inhibition of demethylase by alpha-naphthoflavone in MC-treated microsomes also suggested that cytochrome P-450 species induced by MC are active in demethylating NDMA. The enhancement of NDMA demethylase activity by metyrapone in PB-treated microsomes was greater than in non-treated ones, and was not observed in MC-treated ones. The result is almost the same as in acetanilide hydroxylation, depending on cytochrome P-450. Pyrazole, tranylcypromine, and aminoacetonitrile, which are selective inhibitors of NDMA demethylation, interacted with cytochrome P-450 species to produce type-II spectra, and typical type-II compounds (aniline, imidazole, and nicotinamide) were inhibitors of the NDMA demethylation. Tranylcypromine irreversibly inhibited microsomal monoamine oxidase [EC 1.4.3.4], but not NDMA demethylase. Semicarbazide (a copper- and pyridoxal-containing amine oxidase [EC 1.4.3.6] inhibitor) had no effect on demethylation. From these results it is concluded that NDMA demethylation depends only on cytochrome P-450-dependent monooxygenases.
D000607:Aminoacetonitrile / Q000494:pharmacology; D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D008995:Monoamine Oxidase / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014191:Tranylcypromine / Q000494:pharmacology
D000814:Aniline Compounds; D001571:Benzoflavones; D007093:Imidazoles; D011720:Pyrazoles; D009536:Niacinamide; D000607:Aminoacetonitrile; D014191:Tranylcypromine; C031280:pyrazole; D008748:Methylcholanthrene; C011512:alpha-naphthoflavone; C029899:imidazole; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D019392:Cytochrome P-450 CYP2E1; D008995:Monoamine Oxidase; D010089:Oxidoreductases, N-Demethylating; D000633:Aminopyrine N-Demethylase; C023650:aniline; D010634:Phenobarbital; D008797:Metyrapone