Microsomal metabolism of thiobenzamide and thiobenzamide S-oxide

The oxidation of [3H]thiobenzamide (TB) and its S-oxide (TBSO) has been investigated using rat liver microsomes. In the presence of O2 and NADPH, TB is rapidly converted to TBSO plus small amounts of benzamide (BA) by rat liver microsomes; neither benzonitrile nor other metabolites were detected. Under similar conditions, TBSO is converted solely to BA. Studies with metabolic inhibitors and inducing agents indicated that both the S-oxidation of TB and its further conversion to BA, probably via enzymatic oxidation to TBSO2 (a chemically reactive sulfene), are catalyzed mainly by the microsomal FAD-containing monooxygenase. No clear evidence for the involvement of cytochromes P-450 was obtained, but neither could this possibility be excluded. The overall pathway for biotransformation of TB in vitro can be represented as: TB leads to TBSO leads to [TBSO2] leads to BA. The possible role of TBSO and TBSO2 in the in vivo hepatotoxicity of TB and TBSO are discussed in light of their chemical reactivities.