Vitamin A Potentiation of Vinylidene Chloride Hepatotoxicity in Rats and Precision-Cut Rat Liver Slices

Pretreatment of large doses of vitamin A (VA) is known to potentiatethe hepatotoxicity of carbon tetrachloride. Therefore the effectsof 1-day VA pretreatment on VDC hepatotoxicity was examinedboth in vivo and in an in vitro system of precision-cut ratliver slices. Male Sprague-Dawley rats were pretreated with250,000 IU/kg VA by oral gavage. After 24 hr rats were administered50, 100, or 200 mg/kg VDC ip. Precision-cut liver slices wereprepared from VA pretreated rats 24 hr later and the liver sliceswere exposed for 2–8 hr to 0.025–1.0 µl VDCevaporated into the gas phase of the incubation vials. VA pretreatmentresulted in an enhancement of VDC toxicity, both in vivo andin vitro. There was a dose-dependent increase in plasma ALT24 hr after VDC treatment of rats and an increase in K⁺ leakagefrom liver slices after VDC exposure. Histological analysisof the liver or the liver slices revealed that VA+VDC treatmentresulted in centrilobular necrosis of the liver. When GdCl₃(10 mg/kg iv) was administered just before VA pretreatment ofrats, VDC toxicity was partially reversed as observed by a decreasein ALT in vivo and a decrease in the loss of K⁺ in vitro. Theseresults indicated that Kupffer cells, the resident macrophagesof the liver, were partially responsible for the VA-potentiatedVDC hepatotoxicity. One-day pretreatment of VA induced cytochromeP450IIE1 protein content as well as its enzymatic activity asmeasured by p-nitrophenol hydroxylation. Because VDC is bioactivatedby cytochrome P450IIE1, the increase in VDC hepatotoxicity afterVA may be due to an increased bioactivation of VDC in the liverand in precision-cut liver slices. Thus, more than one mechanismmay be involved in the VA enhancement of VDC hepatotoxicity.