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In vivo administration to rats of the mixed-function oxidase modifiers 3-methylcholanthrene (MC), pregnenolone-16 alpha-carbonitrile (PCN) or beta-naphthoflavnoe (beta-f) inhibits the hepatic microsome-catalyzed in vitro binding of dimethylnitrosamine (DMN) to DNA. This parallels their effect on DMN-demethylase I, regarded to be the sole activating step in DMN carcinogenesis and fails to account for the previously observed anomaly that MC and PCN inhibit, while beta-NF enhances, the hepatocarcinogenic activity of DMN. The in vitro binding of DMN is clearly dependent on microsomes and NADPH, and is strongly enhanced by soluble cytoplasmic proteins; the presence of the latter has no effect. however, on the relative response to pretreatment by the modifiers. In mice beta-NF enhances and PCN inhibits DMN-demethylase I; beta-NF has no effect on either the cytochrome P-450 level or on the LD50, while PCN strongly increases the cytochrome P-450 level but without influencing the LD50. Neither of the two modifiers has any effect in mice on the host-mediated mutagenicity of DMN in a dose-response study, except for the highest dose of DMN (200 mg/kg) where PCN pretreatment significantly enhanced mutagenicity. To account for the anomalous observations, other potential pathways of DMN metabolism have been explored. Whole rat liver nuclei or isolated nuclear membrane fractions contain no DMN-demethylase or diethylnitrosamine-deethylase activity. In a microsomal mixed-function amine-oxidase assay system neither purified enzyme preparations nor whole microsomes catalyze NADPH oxidation in the presence of DMN as substrate. In addition, the purified enzyme does not catalyze formaldehyde production in the DMN-demethylase assay system. Benzylamine, a typical inhibitor of mitochondrial monoamine oxidase (MAO), is a potent inhibitor of DMN-demethylase activity, but microsomes are devoid of MAO activity. Furthermore, purified MAO has no DMN-demethylase activity. The differential effect of modifiers on the carcinogenicity of DMN probably involves pathways other than DMN metabolism.
D Y Lai, and
S C Myers, and
Y T Woo, and
E J Greene, and
M A Friedman, and
M F Argus, and
J C Arcos
June 1982,
Biochemical and biophysical research communications,
D Y Lai, and
S C Myers, and
Y T Woo, and
E J Greene, and
M A Friedman, and
M F Argus, and
J C Arcos
January 1984,
Journal of toxicology and environmental health,
D Y Lai, and
S C Myers, and
Y T Woo, and
E J Greene, and
M A Friedman, and
M F Argus, and
J C Arcos
January 1980,
Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.),
D Y Lai, and
S C Myers, and
Y T Woo, and
E J Greene, and
M A Friedman, and
M F Argus, and
J C Arcos
April 1982,
Biochemical pharmacology,
D Y Lai, and
S C Myers, and
Y T Woo, and
E J Greene, and
M A Friedman, and
M F Argus, and
J C Arcos
April 1982,
Toxicology letters,
D Y Lai, and
S C Myers, and
Y T Woo, and
E J Greene, and
M A Friedman, and
M F Argus, and
J C Arcos
May 1976,
Journal of the National Cancer Institute,
D Y Lai, and
S C Myers, and
Y T Woo, and
E J Greene, and
M A Friedman, and
M F Argus, and
J C Arcos
November 1974,
Mutation research,
D Y Lai, and
S C Myers, and
Y T Woo, and
E J Greene, and
M A Friedman, and
M F Argus, and
J C Arcos
August 1983,
Chemico-biological interactions,
D Y Lai, and
S C Myers, and
Y T Woo, and
E J Greene, and
M A Friedman, and
M F Argus, and
J C Arcos
June 1977,
Zeitschrift fur Krebsforschung und klinische Onkologie. Cancer research and clinical oncology,
D Y Lai, and
S C Myers, and
Y T Woo, and
E J Greene, and
M A Friedman, and
M F Argus, and
J C Arcos
January 1977,
Cancer research,
