Kobayashi S, Murray S, Watson D, Sesardic D, Davies D S, Boobis A R
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, U.K.
Biochem Pharmacol. 1989 Sep 1;38(17):2795-9. doi: 10.1016/0006-2952(89)90433-4.
The kinetics of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in rat and human liver microsomes have been compared. Quinidine is a potent inhibitor of debrisoquine 4-hydroxylase activity of human liver (IC50: 3.6 microM). However, its stereoisomer, quinine, is some 60 times less potent (IC50:223 microM). Both compounds are able to inhibit greater than 95% of 4-hydroxylase activity. In rat liver microsomes quinine is approximately 50 times more potent an inhibitor (IC50:2.4 microM) than quinidine (IC50:137 microM). Again, 4-hydroxylase activity is inhibited by greater than 95%. Inhibition of debrisoquine 4-hydroxylase activity by both quinine and quinidine in human and rat liver is competitive. Values of Ki for quinidine in human and rat were 0.6 microM and 50 microM, whereas with quinidine the Ki values were 13 microM and 1.7 microM, respectively. The data in this paper are consistent with 4-hydroxylation of debrisoquine in both rat and human liver catalysed by a specific form of cytochrome P-450. Although both quinidine and quinine are competitive inhibitors of debrisoquine 4-hydroxylase activity in rat and man, their potency is reversed. This suggests that the nature of the active site of cytochrome P-450dbl differs between the two species, and indicates that data on the specificity of this isoenzyme in the rat should be extrapolated to man with extreme caution.
已比较了奎尼丁和奎宁对大鼠及人肝微粒体中异喹胍4-羟化酶活性的抑制动力学。奎尼丁是人类肝脏异喹胍4-羟化酶活性的强效抑制剂（IC50：3.6微摩尔）。然而，其立体异构体奎宁的效力约低60倍（IC50：223微摩尔）。两种化合物均能抑制超过95%的4-羟化酶活性。在大鼠肝微粒体中，奎宁作为抑制剂的效力（IC50：2.4微摩尔）比奎尼丁（IC50：137微摩尔）高约50倍。同样，4-羟化酶活性被抑制超过95%。奎宁和奎尼丁对人和大鼠肝脏中异喹胍4-羟化酶活性的抑制均为竞争性抑制。奎尼丁在人和大鼠中的Ki值分别为0.6微摩尔和50微摩尔，而奎宁的Ki值分别为13微摩尔和1.7微摩尔。本文数据表明，大鼠和人肝脏中异喹胍的4-羟化均由一种特定形式的细胞色素P-450催化。尽管奎尼丁和奎宁在大鼠和人类中都是异喹胍4-羟化酶活性的竞争性抑制剂，但其效力相反。这表明细胞色素P-450dbl活性位点的性质在这两个物种之间存在差异，并表明关于该同工酶在大鼠中的特异性数据外推至人类时应极其谨慎。
