Tissue specific regulation of renal N-nitrosodimethylamine-demethylase activity by testosterone in BALB/c mice
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1Howard University Cancer Center, Howard University, Washington, DC 20060.
Abstract:
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.
Insights
Nitrosodimethylamine (NDMA) activation in mice kidneys is regulated by age, sex, and hormones, impacting its mutagenic effects. This study correlates NDMA-demethylase activity with mutagenicity, revealing specific isozymes and their hormonal control.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Nitrosodimethylamine (NDMA) is activated by mixed-function oxidases, leading to mutagenic and carcinogenic effects.
- Previous research indicated age, sex, and androgenic regulation of NDMA-induced mutagenicity in BALB/c mice.
Purpose of the Study:
- To investigate the correlation between renal NDMA-demethylase activity and previously reported NDMA-induced mutagenicity.
- To characterize the isozymes of renal NDMA-demethylase and their regulation.
Main Methods:
- Determination of renal and hepatic NDMA-demethylase activities in microsomal fractions by quantifying formaldehyde.
- Analysis of isozyme kinetics (Km values) and their presence/absence based on age, sex, and hormonal treatment (testosterone, castration).
Main Results:
- Renal NDMA-demethylase consists of two isozymes (I and II) with distinct kinetic properties.
- Isozyme I is age- and sex-dependent, appearing at puberty in males and influenced by androgens (testosterone administration, castration).
- Hepatic NDMA-demethylase activity is not affected by age, sex, or testosterone treatment.
Conclusions:
- Renal NDMA-demethylase activity exhibits age, sex, and tissue-specific regulation, primarily influenced by androgenic hormones.
- The observed regulation of renal NDMA-demethylase activity correlates positively with NDMA-induced mutagenesis and carcinogenesis studies.