title: Cocaine-induced kidney toxicity: an in vitro study using primary cultured human proximal tubular epithelial cells.
abstract: Renal failure resulting from cocaine abuse has been well documented, although the underlying mechanisms remain to be investigated. In the present study, primary cultured human proximal tubular epithelial cells (HPTECs) of the kidney were used to investigate its ability to metabolize cocaine, as well as the cytotoxicity induced by cocaine and its metabolites benzoylecgonine (BE), ecgonine methyl ester (EME) and norcocaine (NCOC). Gas chromatography/ion trap-mass spectrometry (GC/IT-MS) analysis of HPTECs exposed to cocaine (1 mM) for 72 h confirmed its metabolism into EME and NCOC, but not BE. EME levels increased along the exposure time to cocaine, while NCOC concentration diminished after reaching a maximum at 6 h, indicating a possible secondary metabolism for this metabolite. Cocaine promoted a concentration-dependent loss of cell viability, whereas BE and EME were found to be non-toxic to HPTECs at the tested conditions. In contrast, NCOC revealed to have higher intrinsic nephrotoxicity than the parent compound. Moreover, cocaine-induced cell death was partially reversed in the presence of ketoconazole (KTZ), a potent CYP3A inhibitor, supporting the hypothesis that NCOC may play a role in cocaine-induced nephrotoxicity. Cocaine-induced cytotoxicity was found to involve intracellular glutathione depletion at low concentrations and to induce mitochondrial damage at higher concentrations. Under the present experimental conditions, HPTECs death pathway followed an apoptotic pattern, which was evident for concentrations as low as 0.1 mM.
authors: REQUIMTE-Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, rua Aníbal Cunha, 164, 4099-030, Porto, Portugal. mjoao.pcv@gmail.com
authors: Maria João
authors: MJ
authors: Valente
authors: Rui
authors: R
authors: Henrique
authors: Vânia
authors: V
authors: Vilas-Boas
authors: Renata
authors: R
authors: Silva
authors: Maria de Lourdes
authors: Mde L
authors: Bastos
authors: Félix
authors: F
authors: Carvalho
authors: Paula
authors: P
authors: Guedes de Pinho
authors: Márcia
authors: M
authors: Carvalho
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000779:Anesthetics, Local / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
chemical_list: D000779:Anesthetics, Local; D000255:Adenosine Triphosphate; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D005978:Glutathione; D003042:Cocaine