DeMaster E G, Shirota F N, Nagasawa H T
Adv Exp Med Biol. 1980;132:219-28. doi: 10.1007/978-1-4757-1419-7_23.
Rat liver microsomes catalyzed the conversion of pargyline (N-methyl-N-propargylbenzylamine) to propiolaldehyde, a potent inhibitor of the low Km mitochondrial aldehyde dehydrogenase (AlDH) isozyme. The involvement of cytochrome P-450 in vivo was shown indirectly by (a) the ability of SKF-525A to block pargyline-induced acetaldehydemia, (b) the prolongation of phenobarbital sleeping time by pargyline, and (c) the enhancement of pargyline-induced acetaldehydemia by phenobarbital pretreatment. Propiolaldehyde was isolated as its semicarbazone by incubating pargyline with either phenobarbital-induced or uninduced rat liver microsomes and an NADPH-generating system, the latter being required for propiolaldehyde formation. In vitro studies with liver mitochondria showed that propiolaldehyde inhibition of AlDH was temperature- and time-dependent and irreversible. We propose that the cytochrome P-450 catalyzed conversion of pargyline to its active metabolite, propiolaldehyde, proceeds via a mechanism involving N-depropargylation, viz., hydroxylation of pargyline alpha to the acetylenic bond forming a carbinolamine intermediate, followed by dissociation.
大鼠肝微粒体催化优降宁（N-甲基-N-炔丙基苄胺）转化为丙炔醛，丙炔醛是低Km线粒体醛脱氢酶（AlDH）同工酶的一种强效抑制剂。细胞色素P-450在体内的参与通过以下方式间接显示：（a）SKF-525A阻断优降宁诱导的乙醛血症的能力；（b）优降宁延长苯巴比妥睡眠时间；（c）苯巴比妥预处理增强优降宁诱导的乙醛血症。通过将优降宁与苯巴比妥诱导或未诱导的大鼠肝微粒体以及一个生成NADPH的系统一起孵育，将丙炔醛分离为其半卡巴腙，生成NADPH的系统是丙炔醛形成所必需的。对肝线粒体的体外研究表明，丙炔醛对AlDH的抑制作用是温度和时间依赖性的且不可逆。我们提出，细胞色素P-450催化优降宁转化为其活性代谢产物丙炔醛，是通过一种涉及N-去炔丙基化的机制进行的，即优降宁在炔键α位发生羟基化形成甲醇胺中间体，随后解离。
