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Author Eldridge, Sandy R. ♦ Covey, Joseph ♦ Morris, Joel ♦ Fang, Bingliang ♦ Horn, Thomas L. ♦ Elsass, Karen E. ♦ Hamre, John R. ♦ McCormick, David L. ♦ Davis, Myrtle A.
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ALKALINE PHOSPHATASE ♦ BIOLOGICAL MARKERS ♦ BLOOD ♦ DOSES ♦ FORMATES ♦ IN VITRO ♦ INDOLES ♦ LIVER ♦ METABOLITES ♦ METHANOL ♦ MOLECULES ♦ NEOPLASMS ♦ ORAL ADMINISTRATION ♦ RATS ♦ TOXICITY ♦ TRANSCRIPTION ♦ UREA ♦ WEIGHT
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 2 days after dosing orally for 2 consecutive days at 100 mg/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 100 mg/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. - Highlights: • NSC-743380 induced biliary hyperplasia in rats. • Toxicity of NSC-743380 appears to be related to its anticancer activity. • The model provides an opportunity to explore biomarkers of biliary hyperplasia.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2014-12-15
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 281
Issue Number 3


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