Pharmacokinetics and metabolism of vinyl fluoride in vivo and in vitro.
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 (Vmax = 0.3 vs 0.1 mg/hr-kg). Both species had an estimated Km of < or = 0.02 mg/liter. The specificity for the oxidation of VF in vivo was 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 investigated in 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 the in vivo data, 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 both in vivo and in vitro may 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 between in vivo and in vitro kinetics in rodents improves. substantially the degree of confidence for human in vivo predictions from in vitro data.
Cantoreggi
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Haskell Laboratory for Toxicology and Industrial Medicine, E.I. du Pont de Nemours and Company, Newark, Delaware 19714, USA.
Keller
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DA
D000280:Administration, Inhalation; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D051381:Rats; D018570:Risk Assessment; D012995:Solubility; D013045:Species Specificity; D013379:Substrate Specificity; D014753:Vinyl Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
D002273:Carcinogens; D007527:Isoenzymes; D014753:Vinyl Compounds; C016829:vinyl fluoride; D019392:Cytochrome P-450 CYP2E1