Xenobiotica. 1998 Nov;28(11):1041-7.  

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

Kurata N, Nishimura Y, Iwase M, Fischer NE, Tang BK, Inaba T, Yasuhara H.

Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.

1. Caucasian liver samples were used in this study. N-demethylation of
trimethadione (TMO) to dimethadione (DMO) was monitored in the presence of
chemical inhibitors of CYPs, such as fluconazole, quinidine,
dimethyl-nitrosamine, acetaminophen, phenacetin, chlorzoxazone and mephenytoin.
Trimethadione N-demethylation was selectively inhibited by dimethylnitrosamine
and chlorzoxazone (> 50%) and weakly inhibited by tolbutamide (12%) and
fluconazole (22%), whereas other inhibitors showed no effect. This result
suggested that TMO metabolism to DMO is mainly mediated by CYP2E1 and marginally
by CYP2C and CYP3A4. 2. Fifteen human livers were screened and interindividual
variability of TMO N-demethylation activity was 3-fold. Chlorzoxazone
6-hydroxylation activity 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 for 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 CYP2E1
and that trimethadione would be a suitable selective probe drug for the
estimation of human CYP2E1 activity in vivo.

PMID: 9879636 [PubMed - indexed for MEDLINE]