Study of the roles of cytochrome P450 (CYPs) in the metabolism and cytotoxicity of perhexiline.
Arch Toxicol
; 96(12): 3219-3231, 2022 12.
Article
en En
| MEDLINE
| ID: mdl-36083301
ABSTRACT
Perhexiline is a prophylactic antianginal agent developed in the 1970s. Although, therapeutically, it remained a success, the concerns of its severe adverse effects including hepatotoxicity caused the restricted use of the drug, and eventually its withdrawal from the market in multiple countries. In the clinical setting, cytochrome P450 (CYP) 2D6 is considered as a possible risk factor for the adverse effects of perhexiline. However, the role of CYP-mediated metabolism in the toxicity of perhexiline, particularly in the intact cells, remains unclear. Using our previously established HepG2 cell lines that individually express 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7) and human liver microsomes, we identified that CYP2D6 plays a major role in the hydroxylation of perhexiline. We also determined that CYP1A2, 2C19, and 3A4 contribute to the metabolism of perhexiline. The toxic effect of perhexiline was reduced significantly in CYP2D6-overexpressing HepG2 cells, in comparison to the control cells. In contrast, overexpression of CYP1A2, 2C19, and 3A4 did not show a significant protective effect against the toxicity of perhexiline. Pre-incubation with quinidine, a well-recognized CYP2D6 inhibitor, significantly attenuated the protective effect in CYP2D6-overexpressing HepG2 cells. Furthermore, perhexiline-induced mitochondrial damage, apoptosis, and ER stress were also attenuated in CYP2D6-overexpressing HepG2 cells. These findings suggest that CYP2D6-mediated metabolism protects the cells from perhexiline-induced cytotoxicity and support the clinical observation that CYP2D6 poor metabolizers may have higher risk for perhexiline-induced hepatotoxicity.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Citocromo P-450 CYP1A2
/
Enfermedad Hepática Inducida por Sustancias y Drogas
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Arch Toxicol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos