Metabolism off Nitrosamines by Purified Rabbit Liver Cytochrome P-450 Isozymes

Chung S. Yang, Yityoong Y. Tu, Dennis R. Koop, Minor J. Coon, Chung S. Yang, Yityoong Y. Tu, Dennis R. Koop, Minor J. Coon

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234 Scopus citations

Abstract

The metabolism of nitrosamines by microsomal cytochrome P-450 (P-450) isozymes was studied in a reconstituted monooxygenase system. P-450 LM2, LM3a, LM3b, and LM3c LM4, and LM6 were purified, respectively, from the livers of phenobarbital-treated, ethanol-treated, untreated, isosafrole-treated, and imida-zole-treated rabbits. Of these isozymes, LM3a had the highest /V-nitrosodimethylamine demethylase (NDMAd) activity with a Km of 2.9 mM and Vmax of 9.3 nmol/min/nmol. LM2, LM4, and LM6 exhibited NDMAd activity only at high A/-nitrosodimethylamine concentrations, and isozymes LM3b, and LM3c had poor activity even at the highest substrate concentrations examined. LM2, however, was more active than LM3a in the metabolism of N-nitrosomethytaniline. With each isozyme (LM3a or LM4), only one Km for NDMAd was observed, whereas with rabbit liver microsomes, multiple Km of 0.07, 0.27, and 36.8 mM were obtained. P-450 isozymes also catalyzed the denitrosation of nitrosamines at rates comparable to or lower than the demethylation, and the ratio of these two reactions was different with different nitrosamines. 2-Phenylethylamine and 3-amino-1,2,4-triazole, which were believed previously to affect NDMAd by mechanisms independent of P-450, were shown to be potent inhibitors of P-450-dependent NDMAd. These results further establish the role of P-450 isozymes in the metabolism of nitrosamines and indicate that LM3a is apparently responsible for the increased N-nitrosodimethylamine metabolism associated with ethanol treatment.

Original languageEnglish (US)
Pages (from-to)1140-1145
Number of pages6
JournalCancer Research
Volume45
Issue number3
StatePublished - Mar 1 1985

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Yang, C. S., Tu, Y. Y., Koop, D. R., Coon, M. J., Yang, C. S., Tu, Y. Y., Koop, D. R., & Coon, M. J. (1985). Metabolism off Nitrosamines by Purified Rabbit Liver Cytochrome P-450 Isozymes. Cancer Research, 45(3), 1140-1145.