Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1.
Article Details
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Kurata N, Nishimura Y, Iwase M, Fischer NE, Tang BK, Inaba T, Yasuhara H
Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1.
Xenobiotica. 1998 Nov;28(11):1041-7.
- PubMed ID
- 9879636 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Chlorzoxazone Cytochrome P450 2E1 Protein Humans UnknownSubstrateInhibitorDetails Paramethadione Cytochrome P450 2C8 Protein Humans UnknownSubstrateDetails Paramethadione Cytochrome P450 2E1 Protein Humans UnknownSubstrateDetails Paramethadione Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Trimethadione Cytochrome P450 2C19 Protein Humans UnknownSubstrateDetails Trimethadione Cytochrome P450 2C8 Protein Humans UnknownSubstrateDetails Trimethadione Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails Trimethadione Cytochrome P450 2E1 Protein Humans UnknownSubstrateDetails Trimethadione Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails