Muakkassah S F, Yang W C
J Pharmacol Exp Ther. 1981 Oct;219(1):147-55.
Aminopyrine N-demethylase was inhibited by phenelzine in vitro and in microsomes isolated from rats treated with phenelzine in vivo. The inhibition was greater if phenelzine was incubated with the microsomal suspension before the addition of the substrate. In vitro, the addition of phenelzine produced immediate decrease in cytochrome P-450. This initial decrease was found to be due to the direct binding of phenelzine to the ferrous heme of cytochrome P-450. Further decrease in cytochrome P-450 occurred upon incubation of microsomes with phenelzine in the presence of NADPH. This secondary decrease in cytochrome P-450 was found to be paralleled by a loss of the home content in cytochrome P-450. The decrease in cytochrome P-450 with concomitant loss of heme can be partially inhibited by a substrate (aminopyrine) or by an inhibitor (metyrapone) of the microsomal enzymes, indicating the possible involvement of the metabolism of phenelzine to a reactive intermediate. The comparison of the effect of phenelzine to that of phenylhydrazine strengthened the possibility that a reactive metabolic intermediate of phenelzine can cause heme destruction in cytochrome P-450. Thus, phenelzine exerts its inhibitory action on microsomal drug metabolism most likely by decreasing the cytochrome P-450 content largely through heme destruction.
氨基比林N-脱甲基酶在体外以及从体内用苯乙肼处理过的大鼠分离出的微粒体中均受到苯乙肼的抑制。如果在添加底物之前将苯乙肼与微粒体悬浮液一起孵育，抑制作用会更强。在体外，添加苯乙肼会使细胞色素P-450立即减少。发现这种最初的减少是由于苯乙肼直接与细胞色素P-450的亚铁血红素结合。在NADPH存在下，微粒体与苯乙肼一起孵育后，细胞色素P-450进一步减少。发现细胞色素P-450的这种二次减少与细胞色素P-450中血红素含量的损失平行。细胞色素P-450的减少以及伴随的血红素损失可被微粒体酶的底物（氨基比林）或抑制剂（甲吡酮）部分抑制，这表明苯乙肼代谢为反应性中间体可能参与其中。将苯乙肼与苯肼的作用进行比较，进一步加强了苯乙肼的反应性代谢中间体可导致细胞色素P-450中血红素破坏的可能性。因此，苯乙肼对微粒体药物代谢的抑制作用很可能主要是通过血红素破坏来降低细胞色素P-450的含量。
