ArticleToxicology reports2021
Species differences in phenobarbital-mediated UGT gene induction in rat and human liver microtissues.
Article in Toxicology reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- A proposal of criteria to support the EU classification on endocrine disruption for the thyroid modality and their application to four data-rich case studies.Archives of toxicology · 2025Article
- A Clinical Nomogram for Predicting Substandard Serum Valproic Acid Concentrations in Chinese Patients With Epilepsy.Current therapeutic research, clinical and experimental · 2025Article
- Therapeutic and Toxic Effects of Valproic Acid Metabolites.Metabolites · 2023Review
- Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization.International journal of molecular sciences · 2022Article
- Physiologically based pharmacokinetic modeling for dose optimization of quinine-phenobarbital coadministration in patients with cerebral malaria.CPT: pharmacometrics & systems pharmacology · 2022Article
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Authors and funding
8 authors.
Funding
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Abstract
Species differences in hepatic metabolism of thyroxine (T4) by uridine diphosphate glucuronosyl transferase (UGT) and susceptibility to thyroid hormone imbalance could underlie differences in thyroid carcinogenesis caused by hepatic enzyme inducers in rats and humans. To investigate this hypothesis we examined profiles of hepatic UGT induction by the prototypical CAR activator phenobarbital (PB) in rat and human liver 3D microtissues. The rationale for this approach was that 3D microtissues would generate data more relevant to humans. Rat and human liver 3D microtissues were exposed to PB over a range of concentrations (500 u M - 2000 u M) and times (24-96 hr). Microarray and proteomics analyses were performed on parallel samples to generate integrated differentially expressed gene (DEG) datasets. Bioinformatics analysis of DEG data, including CAR response element (CRE) sequence analysis of UGT promoters, was used to assess species differences in UGT induction relative to CAR-mediated transactivation potential. A higher proportion of human UGT promoters were found to contain consensus CREs compared to the rat homologs. UGTs 1a6, 2b17 and 2b37 were upregulated by PB in rat liver 3D microtissues, but unaltered in human liver 3D microtissues. By contrast, human UGTs 1A8, 1A10 and 2B10 showed higher levels of induction (RNA and /or protein) compared to the rat homologs. There was general concordance between the presence of CREs and the induction of UGT RNA. As UGT1A and 2B isoforms metabolise T4, these results suggest that differences in UGT induction could contribute to differential susceptibility to CAR-mediated thyroid carcinogenesis in rats and humans.
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