In vitro metabolism of 4-methyl- and 5-methyl-2-mercaptobenzimidazole, thyrotoxic and hepatotoxic rubber antioxidants, in rat liver microsomes

The metabolism of 4-methyl-2-mercaptobenzimidazole (4-MeMBI), 5-methyl-2-mercaptobenzimidazole (5-MeMBI), and 2-mercaptobenzimidazole (MBI) was examined in vitro in rat liver microsomes. The test chemicals were incubated in the presence of liver microsomes from male Sprague-Dawley rats, and their metabolism was analyzed by HPLC. The metabolism amount increased in an incubation time-dependent manner, and was similar among the test chemicals. SKF-525A, a non-selective inhibitor of cytochrome P450 (CYP) enzymes, decreased the metabolic rate of all the test chemicals, indicating the involvement of liver microsomal CYP enzymes. When liver microsomes from rats treated with CYP-inducers (β-naphthoflavone, phenobarbital, and isoniazid) were used, 4-MeMBI was more decreased than 5-MeMBI, particularly in the phenobarbital-treated group. These results, together with the reported inducibility of the drug-metabolizing activity by the test chemicals, partly explained the counteraction in the toxic effects between 4-MeMBI and 5-MeMBI in the in vivo study.