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Nature of N-nitrosodimethylamine demethylase

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Abstract

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 α-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.

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Authors and Affiliations

  1. Division of Pharmacology, Biological Safety Research Center, National Institute of Hygienic Sciences, 1-18-1, Kamiyoga, Setagaya-ku, 158, Tokyo, Japan

    T. Kawanishi, Y. Ohno, A. Takahashi, A. Takanaka & Y. Omori

  2. Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan

    Y. Kasuya

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  1. T. Kawanishi
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  2. Y. Ohno
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  3. A. Takahashi
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  4. A. Takanaka
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  5. Y. Kasuya
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  6. Y. Omori
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Kawanishi, T., Ohno, Y., Takahashi, A. et al. Nature of N-nitrosodimethylamine demethylase. Arch Toxicol 56, 7–11 (1984). https://doi.org/10.1007/BF00316344

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  • DOI: https://doi.org/10.1007/BF00316344

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