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. (2020)

• Record Type: Journal Article
• Authors: Miyajima, Atsuko; Kuroda, Yukie; Sakemi-Hoshikawa, Kazue; Usami, Makoto; Mitsunaga, Katsuyoshi; Irie, Tomohiko; Ohno, Yasuo; Sunouchi, Momoko
• Is Part Of: Toxicology reports. Volume 7(2020)
• Page Start: 979
• Page End: 985
• Publication Date: 2020
• Subjects: MBI 2-mercaptobenzimidazole -- 4-MeMBI 4-methyl-2-mercaptobenzimidazole -- 5-MeMBI 5-methyl-2-mercaptobenzimidazole -- 4(5)-MeMBI 4(or 5)-methyl-2-mercaptobenzimidazole -- CYP cytochrome P450 -- T6βH testosterone 6β-hydroxylation -- EROD 7-ethoxyresorufin O-deethylation -- 3-MC 3-methylcholanthrene -- DMSO dimethyl sulfoxide -- AhR aryl hydrocarbon receptor -- PXR pregnane X receptor; Benzimidazole -- Cytochrome P450 -- Drug-metabolizing activity -- Hepatocyte -- Primary culture; Toxicology -- Periodicals; Clinical toxicology -- Periodicals; Drug-Related Side Effects and Adverse Reactions; Hazardous Substances; Poisoning; Toxicology; Electronic journals; Periodicals; Periodicals; 571.9505
• DOI: 10.1016/j.toxrep.2020.08.003
• Languages: English
• ISSNs: 2214-7500

Abstract

Highlights: 4-MeMBI, 5-MeMBI and MBI inhibit CYP3A2 activity in cultured rat hepatocytes. 4-MeMBI and 5-MeMBI, not MBI, induce CYP1A1/2 activity in cultured rat hepatocytes. Effects of the chemicals on CYP3A2 suggest metabolic drug-drug interaction potential. 4-MeMBI and 5-MeMBI induce CYPs 3A4 and 1A1/2 activity in cultured human hepatocytes. Primary cultured hepatocytes are useful in CYP experiments of benzimidazole compounds. 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 6β-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.