title: Sensitivity to hepatotoxicity due to epigallocatechin gallate is affected by genetic background in diversity outbred mice.
abstract: Consumer use of herbal and dietary supplements has recently grown in the United States and, with increased use, reports of rare adverse reactions have emerged. One such supplement is green tea extract, containing the polyphenol epigallocatechin gallate (EGCG), which has been shown to be hepatotoxic at high doses in animal models. The Drug-Induced Liver Injury Network has identified multiple patients who have experienced liver injury ascribed to green tea extract consumption and the relationship to dose has not been straightforward, indicating that differences in sensitivity may contribute to the adverse response in susceptible people. The Diversity Outbred (DO), a genetically heterogeneous mouse population, provides a potential platform for study of interindividual toxicity responses to green tea extract. Within the DO population, an equal exposure to EGCG (50 mg/kg; daily for three days) was found to be tolerated in the majority of mice; however, a small fraction of the animals (16%; 43/272) exhibited severe hepatotoxicity (10-86.8% liver necrosis) that is analogous to the clinical cases. The data indicate that the DO mice may provide a platform for informing risk of rare, adverse reactions that may occur in consumer populations upon ingestion of concentrated herbal products.
authors.affiliation: Hamner-UNC Institute for Drug Safety Sciences, Durham, NC 27709, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Church
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Gatti
authors.affiliation: Duke University, Durham, NC 27708, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.affiliation: Duke University, Durham, NC 27708, USA.
authors.forename: Nanye
authors.initials: N
authors.lastname: Long
authors.affiliation: U.S. Food and Drug Administration National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: U.S. Food and Drug Administration National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Hamner-UNC Institute for Drug Safety Sciences, Durham, NC 27709, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Eaddy
authors.affiliation: Hamner-UNC Institute for Drug Safety Sciences, Durham, NC 27709, USA.
authors.forename: Merrie
authors.initials: M
authors.lastname: Mosedale
authors.affiliation: North Carolina State University, Raleigh, NC 27607, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Ballard
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.affiliation: Einstein Healthcare Network, Philadelphia, PA 19141, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Navarro
authors.affiliation: Hamner-UNC Institute for Drug Safety Sciences, Durham, NC 27709, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.affiliation: North Carolina State University, Raleigh, NC 27607, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.affiliation: Hamner-UNC Institute for Drug Safety Sciences, Durham, NC 27709, USA. Electronic address: ahharrill@uams.edu.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Harrill
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000009:adverse effects*; D002392:Catechin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D002874:Chromosome Mapping; D004305:Dose-Response Relationship, Drug; D060005:Genotyping Techniques; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D059808:Polyphenols / Q000008:administration & dosage / Q000009:adverse effects*; D040641:Quantitative Trait Loci; D013662:Tea / Q000737:chemistry
chemical_list: D000975:Antioxidants; D059808:Polyphenols; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate
keywords: Diversity outbred; Epigallocatechin gallate; Green tea; Hepatotoxicity; Herbal; Population variability