Gregus Z, Fekete T, Halászi E, Klaassen C D
Department of Pharmacology, University Medical School of Pécs, Hungary.
Drug Metab Dispos. 1996 Jun;24(6):682-8.
Glycine conjugation of benzoic acid is catalyzed by the mitochondrial enzymes benzoyl-coenzyme A(CoA) synthetase and benzoyl-CoA: glycine N-acyltransferase and requires ATP, CoA, and glycine as cosubstrates. Lipoic acid (LA), an important endogenous and also therapeutic compound, depletes hepatic CoA; therefore, it may interfere with glycine conjugation. To test this hypothesis, LA (0.5-1.5 mmol/kg ip) was given to anesthetized, glycine-loaded rats 1 hr before administration of benzoic acid (1 mmol/kg iv). LA inhibited glycine conjugation of benzoic acid in a dose-dependent manner as indicated by: 1) reduced clearance of benzoic acid from blood; 2) delayed appearance of benzoylglycine in blood; and 3) decreased excretion of benzoylglycine in urine. LA also decreased urinary excretion of injected benzoylglycine, indicating that reduced excretion of this metabolite after benzoic acid injection is caused by diminished formation and impaired renal transport of benzoylglycine. Urine formation was decreased by LA in a dose-dependent fashion, and acute renal failure was evident in rats receiving the highest dose. LA depleted hepatic CoA, carnitine, and glutathione, but not ATP, whereas it increased the hepatic concentration of glycine. In isolated and solubilized rat liver mitochondria, LA inhibited both benzoyl-CoA synthetase (IC50 approximately 1.5 mM) and benzoyl-CoA:glycine N-acyltransferase (IC50 approximately 0.3 mM). Thus, depletion of CoA and inhibition of the pertinent enzymes seem responsible for impairment of glycine conjugation of benzoic acid by LA. LA may also impair renal tubular cell function, compromising the tubular secretion of benzoylglycine and causing acute renal failure.
苯甲酸的甘氨酸结合反应由线粒体酶苯甲酰辅酶A（CoA）合成酶和苯甲酰辅酶A：甘氨酸N-酰基转移酶催化，反应需要ATP、CoA和甘氨酸作为共底物。硫辛酸（LA）是一种重要的内源性化合物，同时也是一种治疗性化合物，它会消耗肝脏中的CoA；因此，它可能会干扰甘氨酸结合反应。为了验证这一假设，在给苯甲酸（1 mmol/kg静脉注射）前1小时，给麻醉的、已负载甘氨酸的大鼠腹腔注射LA（0.5 - 1.5 mmol/kg）。LA以剂量依赖性方式抑制苯甲酸的甘氨酸结合反应，表现为：1）血液中苯甲酸清除率降低；2）血液中苯甲酰甘氨酸出现延迟；3）尿液中苯甲酰甘氨酸排泄减少。LA还降低了注射的苯甲酰甘氨酸的尿排泄量，表明苯甲酸注射后该代谢产物排泄减少是由于苯甲酰甘氨酸生成减少和肾脏转运受损所致。LA以剂量依赖性方式减少尿量，接受最高剂量的大鼠出现明显的急性肾衰竭。LA消耗了肝脏中的CoA、肉碱和谷胱甘肽，但未消耗ATP，而它增加了肝脏中甘氨酸的浓度。在分离并溶解的大鼠肝线粒体中，LA抑制苯甲酰辅酶A合成酶（IC50约为1.5 mM）和苯甲酰辅酶A：甘氨酸N-酰基转移酶（IC50约为0.3 mM）。因此，CoA的消耗和相关酶的抑制似乎是LA损害苯甲酸甘氨酸结合反应的原因。LA还可能损害肾小管细胞功能，影响苯甲酰甘氨酸的肾小管分泌并导致急性肾衰竭。
