Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1

1. Caucasian liver samples were used in this study. N-demethylation of trim ethadione (TMO) to dimethadione (DMO) was monitored in the presence of chem ical inhibitors of CYPs, such as fluconazole, quinidine, dimethyl-nitrosami ne, acetaminophen, phenacetin, chlorzoxazone and mephenytoin. Trimethadione N-demethylation was selectively inhibited by dimethylnitrosamine and chlor zoxazone (> 50%) and weakly inhibited by tolbutamide (12 %) and fluconazole (22 %), whereas other inhibitors showed no effect. This result suggested t hat TMO metabolism to DMO is mainly mediated by CYP2E1 and marginally by CY P2C and CYP3A4. 2. Fifteen human livers were screened and interindividual variability of TM O N-demethylation activity was 3-fold. Chlorzoxazone 6-hydroxylation activi ty was also measured and both activities were significantly correlated (r = 0.735, p < 0.01). 3. DMO production by human cDNA expressed CYP enzymes was observed mainly f or CYP2E1 (10.8 nmol/tube), marginally for CYP2C8 (0.22 nmol/tube) and not detectable for other CYP enzymes. 4. These results indicate that TMO metabolism is primarily catalysed by CYP 2E1 and that trimethadione would be a suitable selective probe drug for the estimation of human CYP2E1 activity in vivo.