The nature of microsomal N-nitrosodimethylamine demethylase and its role in carcinogen activation

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Abstract
The subcellular localization of N-nitrosodimethylamine (NDMA) demethylase in rat liver cells and the role of this enzyme in the activation of NDMA were studied. The enzyme activity was predominantly located in the microsomal fraction and the addition of cytosol to the microsomes did not produce a synergistic effect. The microsomal NDMA de-methylase activity appeared to correspond to the ability of the microsomes to convert NDMA to the alkylating species. The alkylation of DNA was assayed by the measurement of O6-methylguanine and 7-methylguanine by fluorescence after isolation by h.p.l.c. The induction of microsomal NDMA de-methylase activity by isopropanol, ethanol, acetone, and fasting was closely related to the increase of DNA methylation by NDMA in an incubation system in vitro. Pretreatment of rats with ethanol, which induced heaptic NDMA demethylase activity, enhanced DNA alkylation in vivo with a high dose of NDMA (75 mg/kg body weight) but not with low doses of NDMA (≤25 mg/kg body weight). The role of NDMA de-methylase in the activation of NDMA is discussed.