Cocaine-induced kidney toxicity: an in vitro study using primary cultured human proximal tubular epithelial cells

• Tipo: Artigo em Revista Científica Internacional
• Data: 2012

Autores

Maria Joao Valente (Autor) Outra; Rui Henrique (Autor) ICBAS; Vania Vilas Boas (Autor) Outra; Renata Silva (Autor) Outra; Maria de Lourdes Bastos (Autor) FFUP; Felix Carvalho (Autor) FFUP; de Pinho, PG (Autor) FFUP; Marcia Carvalho (Autor) Outra

Revista

Título: Archives of Toxicology

Vol. 86

Páginas: 249-261

ISSN: 0340-5761

Editora: Springer Nature

Indexação

ISI Web of Knowledge - 35 Citações

Scopus - 36 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina básica

Outras Informações

ID Authenticus: P-002-DD9

DOI: 10.1007/s00204-011-0749-3

Abstract (EN): 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/ITMS) 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 13