Tissue specific regulation of renal N-nitrosodimethylamine-demethylase activity by testosterone in BALB/c mice.
Nitrosodimethylamine (NDMA), like several other nitrosamines, is activated by the enzymes--mixed-function oxidases--present in the tissue microsomal fractions, producing mutagenic and carcinogenic effects. Previous studies in BALB/c mice have shown an age, sex and androgenic regulation of NDMA-induced mutagenicity. The present study was designed to test the correlation between renal NDMA-demethylase activity and previously published reports on NDMA-induced mutagenicity. Renal and hepatic NDMA-demethylases were determined from the microsomal fractions by quantitating formaldehyde. Renal NDMA-demethylase showed the presence of two isozymes, I and II, with Km values of 0.6 +/- 0.2 and 20.2 +/- 6.8 mM respectively. Isozyme I was detected in adult males and first appeared at the onset of puberty; it was absent in adult females and in immature mice. Renal isozyme II was detected in both males and females and was independent of age. Testosterone treatment of adult females resulted in the appearance of renal isozyme I. Castration of adult males caused a dramatic decrease in activity, whereas testosterone administration to such castrates increased activity, of renal isozyme I. Hepatic NDMA-demethylase activities were independent of age, sex or testosterone treatment. In conclusion, these results show an age, sex and tissue specific regulation of renal NDMA activity. Renal and hepatic NDMA-demethylase activities correlated positively with earlier studies on NDMA-induced mutagenesis and carcinogenesis.
Mohla
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Howard University Cancer Center, Howard University, Washington, DC 20060.
Ahir
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D000367:Age Factors; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D004128:Dimethylnitrosamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009919:Orchiectomy; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D012737:Sex Factors; D013739:Testosterone / Q000502:physiology*
D013739:Testosterone; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D004128:Dimethylnitrosamine