ET-743, an experimental
antitumor drug with promising activity in
sarcoma, breast and ovarian
carcinoma, is currently under phase 2 clinical evaluation. It is hepatotoxic in animals and patients. We tested the hypothesis that
indole-3-carbinol (I3C), the hydrolysis product of
glucosinolates occurring in cruciferous vegetables, may protect against ET-743-induced hepatotoxicity in the female Wistar rat, the animal species with the highest sensitivity toward the adverse hepatic effect of this drug. Hepatotoxicity was adjudged by measurement of plasma levels of
bilirubin,
alkaline phosphatase (ALP) and
aspartate aminotransferase (AST) and by liver histopathology. The effect of I3C on the kinetics of
ET-743 in rat plasma and liver was investigated by high-pressure liquid chromatography. The effect of I3C on the antitumor efficacy of
ET-743 was explored in rats bearing the 13762 mammary
carcinoma.
ET-743 (40 microg/kg i.v.) alone caused an elevation of plasma
bilirubin, ALP and AST levels and degeneration and patchy focal
necrosis of bile duct epithelial cells. Addition of I3C to the diet (0.5%) for 6 days prior to
ET-743 administration almost completely abolished manifestations of hepatotoxicity. In contrast, a dietary concentration of 0.1% I3C did not protect, nor did dietary
diindolylmethane (0.2%), an
acid-catalyzed condensation product of I3C. Ingestion by rats of I3C for 6 days prior to
ET-743 (40 microg/kg i.v.) decreased plasma but not hepatic concentrations of
ET-743 compared to animals that received
ET-743 alone. I3C did not interfere with the antitumor efficacy of
ET-743. The results suggest that ingestion of I3C may counteract the unwanted effect of
ET-743 in the liver. I3C should be investigated as a hepatoprotectant in patients who receive
ET-743 therapy.