Barakat M, El-Kadi A O, Du Souich P
Department of Pharmacology, Faculty of Medicine, Université de Montréal, Québec, Canada.
Drug Metab Dispos. 1997 Feb;25(2):191-5.
It has been shown that selected isoforms of cytochrome P450 (P450) can generate nitric oxide from L-arginine analogs; however, the effect of L-arginine analogs on the catalytic activity of P450 remains unknown. To assess the effect of N-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) and L-arginine (150 mg/kg) on the activity of P450, these compounds were administered intravenously every 8 hr for 2 days to groups of six New Zealand rabbits. Thereafter, the biotransformation of theophylline was documented in vivo (2.5 mg/kg i.v.) and ex vivo in hepatocytes of control and treated animals. In vivo, compared with control rabbits, both L-NAME and L-arginine increased theophylline plasma concentrations secondary to a reduction in theophylline systemic clearance by 46% and 42% (p < 0.05), respectively. Ex vivo, the effect of L-arginine analogs on P450 activity was documented by measuring the production of 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) after incubation of theophylline (176 microM) with hepatocytes for 4 hr. L-NAME reduced the formation of 3MX, 1MU, and 1,3DMU by 42%, 45%, and 32% (p < 0.05), respectively. However, L-arginine reduced only the formation of 3MX by 34% (p < 0.05). In the in vitro studies, incubation of L-NAME or L-arginine with hepatocytes did not modify the biotransformation of theophylline. It is concluded that L-NAME and L-arginine inhibit the activity of several apoenzymes of P450, the probable mechanism being a catalysis-dependent inhibition.
研究表明，细胞色素P450（P450）的某些亚型可从L-精氨酸类似物生成一氧化氮；然而，L-精氨酸类似物对P450催化活性的影响尚不清楚。为评估N-硝基-L-精氨酸甲酯（L-NAME；25mg/kg）和L-精氨酸（150mg/kg）对P450活性的影响，将这些化合物每8小时静脉注射一次，持续2天，给予每组6只新西兰兔。此后，记录了茶碱在体内（2.5mg/kg静脉注射）以及对照组和处理组动物肝细胞的体外生物转化情况。在体内，与对照兔相比，L-NAME和L-精氨酸均使茶碱血浆浓度升高，这是由于茶碱全身清除率分别降低了46%和42%（p<0.05）。在体外，通过在肝细胞中孵育茶碱（176μM）4小时后测量3-甲基黄嘌呤（3MX）、1-甲基尿酸（1MU）和1,3-二甲基尿酸（1,3DMU）的生成，记录了L-精氨酸类似物对P450活性的影响。L-NAME使3MX、1MU和1,3DMU的生成分别减少了42%、45%和32%（p<0.05）。然而，L-精氨酸仅使3MX的生成减少了34%（p<0.05）。在体外研究中，L-NAME或L-精氨酸与肝细胞孵育并未改变茶碱的生物转化。得出的结论是，L-NAME和L-精氨酸抑制了P450几种脱辅基酶的活性，可能的机制是催化依赖性抑制。
