title: Vitamin A potentiation of vinylidene chloride hepatotoxicity in rats and precision-cut rat liver slices.
abstract: Pretreatment of large doses of vitamin A (VA) is known to potentiate the hepatotoxicity of carbon tetrachloride. Therefore the effects of 1-day VA pretreatment on VDC hepatotoxicity was examined both in vivo and in an in vitro system of precision-cut rat liver slices. Male Sprague-Dawley rats were pretreated with 250,000 IU/kg VA by oral gavage. After 24 hr rats were administered 50, 100, or 200 mg/kg VDC ip. Precision-cut liver slices were prepared from VA pretreated rats 24 hr later and the liver slices were exposed for 2-8 hr to 0.025-1.0 microliter VDC evaporated into the gas phase of the incubation vials. VA pretreatment resulted in an enhancement of VDC toxicity, both in vivo and in vitro. There was a dose-dependent increase in plasma ALT 24 hr after VDC treatment of rats and an increase in K+ leakage from liver slices after VDC exposure. Histological analysis of the liver or the liver slices revealed that VA + VDC treatment resulted in centrilobular necrosis of the liver. When GdCl3 (10 mg/kg iv) was administered just before VA pretreatment of rats, VDC toxicity was partially reversed as observed by a decrease in ALT in vivo and a decrease in the loss of K+ in vitro. These results indicated that Kupffer cells, the resident macrophages of the liver, were partially responsible for the VA-potentiated VDC hepatotoxicity. One-day pretreatment of VA induced cytochrome P450IIE1 protein content as well as its enzymatic activity as measured by pnitrophenol hydroxylation. Because VDC is bioactivated by cytochrome P450IIE1, the increase in VDC hepatotoxicity after VA may be due to an increased bioactivation of VDC in the liver and in precision-cut liver slices. Thus, more than one mechanism may be involved in the VA enhancement of VDC hepatotoxicity.
authors.affiliation: Department of Anesthesiology, College of Medicine, University of Arizona, Tucson 85724, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Wueweera
authors.forename: A J
authors.initials: AJ
authors.lastname: Gandolfi
authors.forename: D A
authors.initials: DA
authors.lastname: Badger
authors.forename: I G
authors.initials: IG
authors.lastname: Sipes
authors.forename: K
authors.initials: K
authors.lastname: Brendel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004000:Dichloroethylenes / Q000633:toxicity*; D004357:Drug Synergism; D005682:Gadolinium / Q000494:pharmacology; D006900:Hydroxylation; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014801:Vitamin A / Q000494:pharmacology*
chemical_list: D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004000:Dichloroethylenes; D014801:Vitamin A; C029297:vinylidene chloride; D005682:Gadolinium; D019392:Cytochrome P-450 CYP2E1; C038958:gadolinium chloride