Potentiation of vitamin A hepatotoxicity by butylated hydroxytoluene

The interaction between the natural vitamin A ester retinyl acetate (RA) and the phenolic antioxidant butylated hydroxytoluene (BHT) in the induction of biliary hyperplasia and hepatic fibrosis in female Sprague-Dawley rats was characterized. Using a 3 X 3 matrix design, rats were fed diets supplemented with (per kilogram diet) 0, 125, or 250 mg RA and/or 0, 2500, or 5000 mg BHT. The 125-mg dose of RA induced no gross hepatotoxicity, while the 250-mg dose of RA induced a low incidence of hepatic fibrosis in rats examined after 120 and 180 days of exposure. Exposure to BHT alone induced hepatocellular hypertrophy and dose-related increases in liver weight, but no hepatocellular pathology. Simultaneous administration of RA plus BHT resulted in significant increases in the incidence of biliary hyperplasia and hepatic fibrosis compared to that induced by RA alone. BHT reduced total hepatic vitamin A content at all RA dose levels. Thus, mechanisms other than increases in liver vitamin A levels must underlie the potentiation by BHT of RA hepatotoxicity.