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• W2082168814 abstract "Vinyl fluoride (VF) is an inhalation carcinogen at concentrations of 25 ppm or greater in rats and mice. The main neoplastic lesion induced in rodents was hepatic hemangiosarcomas, and mice were more sensitive than rats. In a first set of experiments, groups of three rats or five mice were exposed to VF in a closed-chamber gas uptake system at starting concentrations ranging from 50 to 250 ppm. Chamber concentrations of VF were measured every 10–12 min by gas chromatography. Partition coefficients were determined by the vial equilibration technique and used as parameters for a physiologically based pharmacokinetic (PBPK) model. Mice showed a higher whole-body metabolic capacity compared to rats (Vmaxc= 0.3 vs 0.1 mg/hr-kg). Both species had an estimatedKmof ≤0.02 mg/liter. The specificity for the oxidation of VFin vivowas determined by selective inhibition or induction of CYP 2E1. Inhibition with 4-methylpyrazole completely impaired VF uptake in rats and mice, whereas induction with ethanol (rats only) increased the metabolic capacity by two- to threefold. The pharmacokinetics of VF were also investigatedin vitro.Microsomes from rat and mouse liver were incubated in a sealed vial with VF and an NADPH- regenerating system. Headspace concentrations (10–300 ppm) were monitored over time by gas chromatography. Consistent with thein vivodata, VF was metabolized faster by mouse microsomes than by rat microsomes (Vmax= 3.5 and 1.1 nmol/hr-mg protein, respectively). The rates of metabolism by human liver microsomes were generally in the same range as those found with rat liver microsomes (Vmax= 0.5–1.3 nmol/hr-mg protein), but one sample was similar to mice (Vmax= 3.3 nmol/hr-mg protein). Metabolic rates in human microsomes were found to correlate with the amount of CYP 2E1 as determined by Western blotting and by chlorzoxazone 6-hydroxylation. It is concluded that the greater metabolic capacity of mice for VF bothin vivoandin vitromay contribute to their greater susceptibility to tumor formation. CYP 2E1 is clearly the main isozyme involved in the oxidation of VF in all species tested. VF pharmacokinetics and metabolism in humans may depend upon the interindividual variability in the expression level of CYP 2E1. The excellent correspondence betweenin vivoandin vitrokinetics in rodents improves substantially the degree of confidence for humanin vivopredictions fromin vitrodata." @default.
• W2082168814 created "2016-06-24" @default.
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• W2082168814 date "1997-03-01" @default.
• W2082168814 modified "2023-10-08" @default.
• W2082168814 title "Pharmacokinetics and Metabolism of Vinyl Fluoridein Vivoandin Vitro" @default.
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• W2082168814 doi "https://doi.org/10.1006/taap.1996.8041" @default.
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