Moloney S J, Prough R A
Arch Biochem Biophys. 1983 Mar;221(2):577-84. doi: 10.1016/0003-9861(83)90178-9.
The oxidative metabolism of procarbazine, its azo, hydrazone, and two azoxy derivatives, and methylhydrazine by hepatic microsomes from phenobarbital-pretreated rats was investigated to elucidate the pathway of metabolism that resulted in methane formation from procarbazine. When incubated with microsomal reaction mixtures fortified with NADPH, all of the compounds, except the azoxy isomers, were metabolized to yield methane. A lag phase in methane formation was noted for procarbazine, but not for the other compounds. Kinetic and inhibition studies utilizing methimazole and ethylhydrazine precluded methylhydrazine as an intermediate in methane formation from procarbazine. When the azo derivative was oxidatively metabolized in the presence of liver microsomes, no hydrazone tautomer was detected. Upon monitoring the production of the azo and hydrazone metabolites formed during microsomal metabolism of procarbazine, the azo derivative was formed in sufficient quantities to account for the majority of the methane produced. In addition, small amounts of hydrazone were also detected. It was concluded that both the azo and hydrazone metabolites of procarbazine contribute to methane formation from the terminal methyl group of the hydrazine with the azo derivative being the predominant source and the hydrazone derivative being a minor source of methane. Consideration of the chemical and enzymatic pathways of procarbazine oxidation and the implication of a methyl radical intermediate in methane formation are discussed.
研究了苯巴比妥预处理大鼠肝脏微粒体对丙卡巴肼、其偶氮、腙和两种氧化偶氮衍生物以及甲基肼的氧化代谢，以阐明导致丙卡巴肼生成甲烷的代谢途径。当与用NADPH强化的微粒体反应混合物一起孵育时，除氧化偶氮异构体外，所有化合物均被代谢生成甲烷。丙卡巴肼在甲烷生成过程中出现了一个滞后期，而其他化合物则没有。利用甲巯咪唑和乙肼进行的动力学和抑制研究排除了甲基肼是丙卡巴肼生成甲烷过程中的中间体。当偶氮衍生物在肝脏微粒体存在下进行氧化代谢时，未检测到腙互变异构体。在监测丙卡巴肼微粒体代谢过程中形成的偶氮和腙代谢产物的产生时，偶氮衍生物的生成量足以解释所产生甲烷的大部分。此外，还检测到少量的腙。得出的结论是，丙卡巴肼的偶氮和腙代谢产物均有助于从肼的末端甲基生成甲烷，其中偶氮衍生物是主要来源，腙衍生物是甲烷的次要来源。讨论了丙卡巴肼氧化的化学和酶促途径以及甲基自由基中间体在甲烷形成中的意义。
