title: 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 2 days 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.
authors.affiliation: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20892, USA.
authors.forename: Sandy R
authors.initials: SR
authors.lastname: Eldridge
authors.affiliation: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20892, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Covey
authors.affiliation: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20892, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Morris
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
authors.affiliation: IIT Research Institute, Chicago, IL, 60616, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Horn
authors.affiliation: Battelle Columbus, Columbus, OH, 43201, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Elsass
authors.affiliation: Investigative Toxicology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Hamre
authors.affiliation: IIT Research Institute, Chicago, IL, 60616, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: McCormick
authors.affiliation: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20892, USA. Electronic address: myrtledavis@mail.nih.gov.
authors.forename: Myrtle A
authors.initials: MA
authors.lastname: Davis
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D001659:Biliary Tract / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001660:Biliary Tract Diseases / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D006965:Hyperplasia; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D011897:Random Allocation; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
chemical_list: C000595256:1-((3-chlorophenyl)methyl)-1H-indole-3-carbinol; D000970:Antineoplastic Agents; D015415:Biomarkers; D015507:Drugs, Investigational; D007211:Indoles; C000595257:NSC-741908; C000595258:NSC-751172
keywords: Biliary hyperplasia; Hepatotoxicity; Indole-3-carbinol; Rat liver