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

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. I...

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Bibliographic Details
Published in:Toxicology and applied pharmacology 2014-12, Vol.281 (3), p.303-309
Main Authors: Eldridge, Sandy R., Covey, Joseph, Morris, Joel, Fang, Bingliang, Horn, Thomas L., Elsass, Karen E., Hamre, John R., McCormick, David L., Davis, Myrtle A.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Acute Disease
Administration, Oral
ALKALINE PHOSPHATASE
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - adverse effects
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacokinetics
Biliary hyperplasia
Biliary Tract - drug effects
Biliary Tract - metabolism
Biliary Tract - pathology
Biliary Tract Diseases - blood
Biliary Tract Diseases - chemically induced
Biliary Tract Diseases - metabolism
Biliary Tract Diseases - pathology
Biological and medical sciences
BIOLOGICAL MARKERS
Biomarkers - blood
Biotransformation
BLOOD
Chemical and Drug Induced Liver Injury - blood
Chemical and Drug Induced Liver Injury - metabolism
Chemical and Drug Induced Liver Injury - pathology
Chemical and Drug Induced Liver Injury - physiopathology
Dose-Response Relationship, Drug
DOSES
Drug Evaluation, Preclinical - methods
Drugs, Investigational - administration & dosage
Drugs, Investigational - adverse effects
Drugs, Investigational - metabolism
Drugs, Investigational - pharmacokinetics
FORMATES
Hepatotoxicity
Hyperplasia
IN VITRO
Indole-3-carbinol
INDOLES
Indoles - administration & dosage
Indoles - adverse effects
Indoles - blood
Indoles - metabolism
Indoles - pharmacokinetics
LIVER
Liver - drug effects
Liver - metabolism
Liver - pathology
Liver - physiopathology
Male
Medical sciences
METABOLITES
METHANOL
MOLECULES
NEOPLASMS
ORAL ADMINISTRATION
Random Allocation
Rat liver
RATS
Rats, Inbred F344
Structure-Activity Relationship
TOXICITY
Toxicology
TRANSCRIPTION
UREA
WEIGHT
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Summary: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. •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:0041-008X
1096-0333
1096-0333
DOI:10.1016/j.taap.2014.10.015