Molecular mechanism of chemical-induced toxicity in fetal livers

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We found several new results of drug metabolism in human liver microsomes. 1) Voriconazole ((2R, 3S)-2-(2, 4-difluorophenyI)-3-(5-fluoro-4-pyrimidiny1)-1-(1H-1, 2, 4-triazol-1-yl)-2-butanol) is a new antifungal agent developed as oral and intravenous formulations. In vivo studies in humans have indicated that voriconazole is extensively metabolized with less than 2% of the dose excreted unchanged. Involvement of cytochrome CYP2C19, CYP2C9, and CYP3A4 in N-oxidation of voriconazole has been demonstrated using human liver microsomes. To confirm the precise roles of P450 isoforms in voriconazole clearance in individuals, we investigated the oxidative metabolism of voriconazole catalyzed by recombinant P450s as well as human liver microsomes genotyped for the CYP2C19 gene. Among recombinant P450 isoforms using Escherichia coli expression systems, CYP2C19 and CYP3A4 had voriconazole N-oxidation activities, but not CYP2C92) Propofol (2, 6-diisopropylphenol) is administered for the induction … More of anesthesia and maintenance of anesthesia or for sedation. The merit of rapid and complete recovery that occurs even after relatively prolonged intravenous infusions of propofol is attributable to the extensive biotransformation of the parent compound, primarily in the liver. However, a significant association with the development of progressive myocardial failure has been reported for long-term and high-dose propofol infusion. Although there are several reports on the propofol pharmacokinetics and drug interactions in humans, the roles of individual P450 enzymes in the propofol disposition are still unknown. In the present study, the roles of human P450 enzymes involved in propofol 4- and ω-hydroxylation were investigated with recombinant human P450s and liver microsomes. CYP2B6 and CYP1A2, followed CYP3A4, showed high activities of propofol 4-hydroxylation in recombinant human P450 enzyme systems. In the contrast, ω-hydroxylation of propofol was mainly catalyzed by CYP2B6.3) Thalidomide is a promising drug in the treatment of a number of cancers and inflammatory diseases. On the other hand, a little information was reported regarding effects on metabolizing enzymes. We investigated the effects of thalidomide on cytochrome P450 in human liver microsomes. The present results suggest that total midazolam clearance would be increased in a dose dependent manner. Thalidomide may cause drug interactions of co-administered medicines Less