Tu Y Y, Peng R, Chang Z F, Yang C S
Chem Biol Interact. 1983 Jun;44(3):247-60. doi: 10.1016/0009-2797(83)90053-4.
The effects of acetone and isopropanol on the microsomal monooxygenase system have been investigated to study the role of this enzyme system in the metabolism of nitrosamines. Treatment of rats with acetone or isopropanol (2.5-5 ml/kg, i.g.) causes a 3-4.5-fold enhancement in the NADPH-dependent nitrosodimethylamine demethylase (NDMAd) activity. This is accompanied by only moderate increases in the gross cytochrome P-450 (P-450) content and NADPH-cytochrome c reductase activity. Several other monooxygenase activities were increased to different extents from an 8% increase in aryl hydrocarbon hydroxylase to a 261% increase in ethoxycoumarin O-dealkylase activities. Kinetic analysis indicates that a low Km form of NDMAd (Km = 0.07 mM) is induced by these treatments. In the microsomes of the treated rats, this high affinity form becomes predominant, in contrast to control microsomes which possess at least three Km-values for NDMAd. The treatment also enhances the metabolism of nitrosomethylethylamine, nitrosomethylbenzylamine and nitrosomethylaniline although to lesser extents than with nitrosodimethylamine. Several lines of observations suggest that the enhanced NDMAd is due to the induction of one or more specific P-450 isozyme(s) by pretreatment with acetone or isopropanol: (a) The treatment induces proteins with molecular weights (Mr) of 50 000 and 52 000 which are in the range of known P-450 isozymes. (b) The induction of these proteins and NDMAd activity was inhibited by CoCl2 and cycloheximide. (c) The induced microsomes had a peak at 450.6 nm different from the 450.0 nm peak of control microsomes. When added to the incubation mixture, both acetone and isopropanol inhibit NDMAd activity. Isopropanol is more potent than acetone and is shown to be a competitive inhibitor with a Ki-value of 0.151 mM.
为了研究微粒体单加氧酶系统在亚硝胺代谢中的作用，人们对丙酮和异丙醇对该酶系统的影响进行了研究。用丙酮或异丙醇（2.5 - 5 ml/kg，腹腔注射）处理大鼠，会使依赖于NADPH的亚硝基二甲胺脱甲基酶（NDMAd）活性提高3 - 4.5倍。与此同时，细胞色素P - 450（P - 450）总量和NADPH - 细胞色素c还原酶活性仅适度增加。其他几种单加氧酶活性也有不同程度的提高，从芳烃羟化酶活性提高8%到乙氧香豆素O - 脱烷基酶活性提高261%。动力学分析表明，这些处理诱导出一种低Km形式的NDMAd（Km = 0.07 mM）。在经处理大鼠的微粒体中，这种高亲和力形式占主导地位，而对照微粒体对NDMAd至少有三个Km值。该处理还增强了甲基乙基亚硝胺、甲基苄基亚硝胺和甲基苯胺亚硝胺的代谢，尽管程度低于亚硝基二甲胺。多项观察结果表明，NDMAd活性增强是由于丙酮或异丙醇预处理诱导了一种或多种特定的P - 450同工酶：（a）该处理诱导出分子量（Mr）为50000和52000的蛋白质，它们在已知P - 450同工酶的范围内。（b）这些蛋白质和NDMAd活性的诱导被CoCl2和环己酰亚胺抑制。（c）诱导的微粒体在450.6 nm处有一个峰，不同于对照微粒体在450.0 nm处的峰。当添加到孵育混合物中时，丙酮和异丙醇都会抑制NDMAd活性。异丙醇比丙酮更有效，显示为竞争性抑制剂，Ki值为0.151 mM。
