Characterization of acute biliary hyperplasia in Fisher 344 Rats administered the Indole-3-Carbinol Analog, NSC-743380

Abstract

NSC-743380 (1-[(3-chlorophenyl)-methyl]-1H-indole-3-carbinol) is in early stages of development as an anticancer agent. Two metabolites reflect sequential conversion of the carbinol functionality to a carboxaldehyde and the major metabolite, 1-[(3-chlorophenyl)-methyl]-1H-indole-3-carboxylic acid. In an exploratory toxicity study in rats, NSC-743380 induced elevations in liver-associated serum enzymes and biliary hyperplasia. Biliary hyperplasia was observed 2days after dosing orally for 2 consecutive days at 100mg/kg/day. Notably, hepatotoxicity and biliary hyperplasia were observed after oral administration of the parent compound, but not when major metabolites were administered. The toxicities of a structurally similar but pharmacologically inactive molecule and a structurally diverse molecule with a similar efficacy profile in killing cancer cells in vitro were compared to NSC-743380 to explore scaffold versus target-mediated toxicity. Following two oral doses of 100mg/kg/day given once daily on two consecutive days, the structurally unrelated active compound produced hepatic toxicity similar to NSC-743380. The structurally similar inactive compound did not, but, lower exposures were achieved. The weight of evidence implies that the hepatotoxicity associated with NSC-743380 is related to the anticancer activity of the parent molecule. Furthermore, because biliary hyperplasia represents an unmanageable and non-monitorable adverse effect in clinical settings, this model may provide an opportunity for investigators to use a short-duration study design to explore biomarkers of biliary hyperplasia.