This study was conducted to examine the involvement of cytochrome P450 (CYP450) and the flavin-containing monooxygenase (FMO) in the sulphoxidation of ethyl methyl sulphide (EMS), 4-chlorophenyl methyl sulphide (CPMS) and diphenyl sulphide (DPS) in human liver microsomes from a phenotypic CYP2D6 extensive metabolizer. Human liver microsomes catalyzed the sulphoxidation of EMS, CPMS and DPS to their corresponding sulphoxides. Lineweaver-Burk plots for the sulphoxidation of EMS in human liver microsomes indicated that the apparent K(m) and V(max) were 1.53 +/- 0.07 mM and 1.11 +/- 0.25 nmoles/mg protein/min, respectively. The apparent K(m) and V(max) for the sulphoxidation of CPMS were 0.17 +/- 0.05 mM and 1.41 +/- 0.16 nmoles/mg protein/min, respectively. The apparent K(m) and V(max) for the sulphoxidation of DPS were 0.10 +/- 0.01 mM and 1.08 +/- 0.05 nmoles/mg protein/min, respectively. Methimazole noncompetitively inhibited the sulphoxidation of EMS, CPMS and DPS by human liver microsomes with K(i) values of 8.6 +/- 0.6, 5.7 +/- 0.4 and 6.6 +/- 0.5 mM, respectively. SKF525A noncompetitively inhibited the sulphoxidation of CPMS and DPS by human liver microsomes with K(i) values of 6.6 +/- 0.4 and 0.40 +/- 0.1 mM, respectively. The results suggest that FMO is involved in the sulphoxidation of EMS, CPMS and DPS while CYP450 is involved in the sulphoxidation of CPMS and DPS in human liver microsomes.