Mohla S, Ahir S, Ampy F R
Howard University Cancer Center, Howard University, Washington, DC 20060.
Biochem Pharmacol. 1988 Jul 1;37(13):2697-702. doi: 10.1016/0006-2952(88)90265-1.
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.
二甲基亚硝胺（NDMA）与其他几种亚硝胺一样，可被组织微粒体组分中存在的混合功能氧化酶激活，产生致突变和致癌作用。先前对BALB/c小鼠的研究表明，NDMA诱导的致突变性存在年龄、性别和雄激素调节。本研究旨在测试肾NDMA去甲基酶活性与先前发表的关于NDMA诱导致突变性的报告之间的相关性。通过定量甲醛从微粒体组分中测定肾和肝的NDMA去甲基酶。肾NDMA去甲基酶显示存在两种同工酶，I和II，其Km值分别为0.6±0.2和20.2±6.8 mM。同工酶I在成年雄性中检测到，在青春期开始时首次出现；在成年雌性和未成熟小鼠中不存在。肾同工酶II在雄性和雌性中均检测到，且与年龄无关。对成年雌性进行睾酮治疗导致肾同工酶I出现。成年雄性去势导致肾同工酶I的活性急剧下降，而对这些去势动物给予睾酮则增加其活性。肝NDMA去甲基酶活性与年龄、性别或睾酮治疗无关。总之，这些结果表明肾NDMA活性存在年龄、性别和组织特异性调节。肾和肝的NDMA去甲基酶活性与先前关于NDMA诱导的诱变和致癌作用的研究呈正相关。
