title: Contribution of oxidative metabolism to cocaine-induced liver and kidney damage.
abstract: 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.
authors.affiliation: REQUIMTE, Laboratorio de Toxicologia, Departamento de Ciencias Biologicas, Faculdade de Farmacia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. mjoao.pcv@gmail.com
authors.forename: M J
authors.initials: MJ
authors.lastname: Valente
authors.forename: F
authors.initials: F
authors.lastname: Carvalho
authors.forename: M d L
authors.initials: Md
authors.lastname: Bastos
authors.forename: P G
authors.initials: PG
authors.lastname: de Pinho
authors.forename: M
authors.initials: M
authors.lastname: Carvalho
mesh_terms: D000818:Animals; D003042:Cocaine / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D018765:Dopamine Uptake Inhibitors; D017382:Reactive Oxygen Species; D003042:Cocaine