REQUIMTE, Laboratorio de Toxicologia, Departamento de Ciencias Biologicas, Faculdade de Farmacia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Curr Med Chem. 2012;19(33):5601-6. doi: 10.2174/092986712803988938.
Cocaine is a potent psychoactive illicit substance and its abuse represents a major health burden worldwide. The pharmacodynamics and toxicity of cocaine have been extensively documented, and are generally associated to its affinity towards neurotransmitters transporters and several receptors. However, drug-related formation of reactive compounds, as is the case of pro-oxidant reactive species, and interaction at molecular level is still an understudied matter. The involvement of oxidative stress (OS) in cocaine-induced toxicity has been reported in both human and animal models, in several organs and systems, including heart, liver, kidney, and central nervous system (CNS). Cytochrome P450 (CYP450)-mediated cocaine metabolism yields the reactive pro-oxidant compound norcocaine (NCOC) and further oxidative metabolites. Special emphasis should be given to the stable radical norcocaine nitroxide (NCOC-NO·), which plays a key role in cocaine-induced hepatotoxicity, either by entering a futile redox cycle with an N-oxidative metabolite, or by being further oxidized to a highly reactive ion. In fact, cocaine-induced generation of reactive oxygen species (ROS) and consequent OS has been postulated based on the reactivity of cocaine N-oxidative metabolites. Depletion of cellular antioxidant defenses and impairment of mitochondrial respiration have also been considered important causes of ROS production, and subsequent cell death mediated by cocaine. The present review provides a thorough description of the current knowledge on cocaine oxidative metabolism and its role on drug-induced liver and kidney damage.
可卡因是一种强效的精神活性非法物质，其滥用给全球带来了巨大的健康负担。可卡因的药效学和毒性已得到广泛的记录，通常与其对神经递质转运体和几种受体的亲和力有关。然而，与药物相关的反应性化合物的形成，如促氧化剂反应性物质，以及在分子水平上的相互作用，仍然是一个研究不足的问题。在人类和动物模型中，在心脏、肝脏、肾脏和中枢神经系统（CNS）等多个器官和系统中，已经报道了氧化应激（OS）在可卡因诱导的毒性中的参与。细胞色素 P450（CYP450）介导的可卡因代谢产生反应性促氧化剂化合物去甲可卡因（NCOC）和进一步的氧化代谢物。特别需要强调的是，稳定的自由基去甲可卡因亚硝化物（NCOC-NO·），它在可卡因诱导的肝毒性中起着关键作用，要么通过与 N-氧化代谢物进入无效的氧化还原循环，要么通过进一步氧化成高度反应性的离子。事实上，基于可卡因 N-氧化代谢物的反应性，已经提出了可卡因诱导的活性氧（ROS）产生和随后的 OS。细胞抗氧化防御的耗竭和线粒体呼吸的损害也被认为是 ROS 产生的重要原因，随后可卡因介导的细胞死亡。本综述提供了可卡因氧化代谢及其在药物诱导的肝和肾损伤中的作用的最新知识的全面描述。
