Boelsterli Urs A
HepaTox Consulting, CH-4148 Pfeffingen, and Institute of Clinical Pharmacy, University of Basel, Basel, CH-4031, Switzerland.
Curr Drug Metab. 2002 Aug;3(4):439-50. doi: 10.2174/1389200023337315.
Some carboxylic acid-containing drugs have been implicated in rare but serious adverse reactions. These compounds can be bioactivated via two distinct pathways: by UDP-glucuronosyltransferase-catalyzed conjugation with glucuronic acid, resulting in the formation of acyl glucuronides, or by acyl-CoA synthetase-catalyzed formation of acyl-CoA thioesters. This review compares the two types of potentially reactive metabolites with respect to their stability, protein-reactivity, target selectivity, and disposition in the liver, and summarizes the evidence which links acyl glucuronide and acyl-CoA thioester formation with downstream toxicologic effects. While with increasing drug concentration the acyl glucuronide pathway may prevail, CoA intermediates may be more reactive. Both metabolites are electrophilic species which can acylate target proteins if they escape inactivation by S-glutathione-thioester formation. A crucial factor is the up-concentration of acyl glucuronides in hepatocytes and the biliary tree, due to vectorial transport by conjugate export pumps, where they may selectively acylate canalicular membrane proteins. Furthermore, positional isomers, which are avidly formed by acyl migration, can glycate proteins in the liver and at more distal sites. In contrast, acyl-CoA esters may be more rapidly hydrolysed or further metabolized in hepatocytes, and their hepatobiliary transport has not been well explored. While there is accumulating evidence that acyl glucuronides can alter cellular function by various mechanisms, including haptenation of peptides, critical protein acylation or glycation, or direct stimulation of neutrophils and macrophages, the role of acyl-CoA intermediates is less clear. More work is needed to provide a causal link between protein-reactive acyl glucuronides and acyl-CoA thioesters and the rare and unpredictable idiosyncratic drug reactions in humans.
一些含羧酸的药物与罕见但严重的不良反应有关。这些化合物可通过两种不同途径进行生物活化：通过尿苷二磷酸葡萄糖醛酸基转移酶催化与葡萄糖醛酸结合，形成酰基葡萄糖醛酸；或通过酰基辅酶A合成酶催化形成酰基辅酶A硫酯。本综述比较了这两种潜在反应性代谢物在稳定性、蛋白质反应性、靶点选择性以及在肝脏中的处置等方面的差异，并总结了将酰基葡萄糖醛酸和酰基辅酶A硫酯形成与下游毒理学效应联系起来的证据。虽然随着药物浓度的增加，酰基葡萄糖醛酸途径可能占主导，但辅酶A中间体可能更具反应性。这两种代谢物都是亲电物质，如果它们不能通过形成S-谷胱甘肽硫酯而失活，就可以酰化靶蛋白。一个关键因素是由于共轭物输出泵的向量转运，酰基葡萄糖醛酸在肝细胞和胆管树中的浓度升高，在那里它们可能选择性地酰化胆小管膜蛋白。此外，通过酰基迁移大量形成的位置异构体可以在肝脏和更远端的部位使蛋白质糖化。相比之下，酰基辅酶A酯可能在肝细胞中更快地水解或进一步代谢，并且它们的肝胆转运尚未得到充分研究。虽然越来越多的证据表明酰基葡萄糖醛酸可以通过多种机制改变细胞功能, 包括肽的半抗原化、关键蛋白的酰化或糖化，或直接刺激中性粒细胞和巨噬细胞，但酰基辅酶A中间体的作用尚不清楚。需要更多的研究来建立蛋白质反应性酰基葡萄糖醛酸和酰基辅酶A硫酯与人类罕见且不可预测的特异质药物反应之间的因果联系。
