Inhibitory and inductive effects of 4- or 5-methyl-2-mercaptobenzimidazole, thyrotoxic and hepatotoxic rubber antioxidants, on several forms of cytochrome P450 in primary cultured rat and human hepatocytes.
Toxicol Rep
; 7: 979-985, 2020.
Article
en En
| MEDLINE
| ID: mdl-32874920
ABSTRACT
Effects of 4-methyl-2-mercaptobenzimidazole (4-MeMBI) and 5-methyl-2- mercaptobenzimidazole (5-MeMBI) on cytochrome P450 (CYP) activity were examined in primary cultured rat hepatocytes. Hepatocytes from male Wistar rats were cultured in the presence of 4-MeMBI or 5-MeMBI (0-400 µM), and the activity of CYPs 3A2/4 (48 and 96 h) and 1A1/2 (48 h) was determined by measuring the activity of testosterone 6ß-hydroxylation and 7-ethoxyresorufin O-deethylation, respectively. As a result, 4-MeMBI and 5-MeMBI (≥12.5 µM) inhibited CYP3A2 activity. On the other hand, 4-MeMBI (≥25 µM) and 5-MeMBI (≥100 µM) induced CYP1A1/2 activity, being consistent with the previous in vivo results. In a comparative metabolism study using primary cultured human hepatocytes from two Caucasian donors, 4-MeMBI and 5-MeMBI induced the activity of CYPs 3A4 and 1A1/2 with individual variability. It was concluded from these results that 4-MeMBI, 5-MeMBI and MBI caused inhibition of CYP3A2 activity in primary cultured rat hepatocytes, suggesting their potential for metabolic drug-drug interactions. Primary cultured rat and human hepatocytes were considered to be useful for the evaluation of effects of the benzimidazole compounds on their inducibility and inhibitory activities of cytochrome P450 forms.
3-MC, 3-methylcholanthrene; 4(5)-MeMBI, 4(or 5)-methyl-2-mercaptobenzimidazole; 4-MeMBI, 4-methyl-2-mercaptobenzimidazole; 5-MeMBI, 5-methyl-2-mercaptobenzimidazole; AhR, aryl hydrocarbon receptor; Benzimidazole; CYP, cytochrome P450; Cytochrome P450; DMSO, dimethyl sulfoxide; Drug-metabolizing activity; EROD, 7-ethoxyresorufin O-deethylation; Hepatocyte; MBI, 2-mercaptobenzimidazole; PXR, pregnane X receptor; Primary culture; T6ßH, testosterone 6ß-hydroxylation
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1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Toxicol Rep
Año:
2020
Tipo del documento:
Article
País de afiliación:
Japón