Species differences in phenobarbital-mediated UGT gene induction in rat and human liver microtissues
| العنوان: | Species differences in phenobarbital-mediated UGT gene induction in rat and human liver microtissues |
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| المؤلفون: | Elizabeth F. McInnes, Stephanie Wallace, David Cowie, Simon Plummer, Matthew Elcombe, Richard A. Currie, Bobby Beaumont, Jayne Wright |
| المصدر: | Toxicology Reports, Vol 8, Iss, Pp 155-161 (2021) Toxicology Reports |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Gene isoform, Health, Toxicology and Mutagenesis, Liver microtissues, 010501 environmental sciences, Toxicology, medicine.disease_cause, digestive system, 01 natural sciences, 03 medical and health sciences, Transactivation, chemistry.chemical_compound, 0302 clinical medicine, Cross species risk assessment, RA1190-1270, Gene expression, medicine, Uridine glucuronosyltransferase, ComputingMethodologies_COMPUTERGRAPHICS, 0105 earth and related environmental sciences, Chemistry, Activator (genetics), Regular Article, Promoter, Genomics, Molecular biology, Uridine diphosphate, Toxicology. Poisons, Carcinogenesis, Thyroid carcinogenesis, 030217 neurology & neurosurgery, Drug metabolism |
| الوصف: | Graphical abstract Highlights • Species differences in UGT induction could mediate thyroid cancer susceptibility. • The effect of CAR activators on rat thyroid carcinogenesis could be partly explained by differential induction of Ugt 2b17. • Human UGT changes would likely contribute less to species differences in T4 metabolism than rat UGT changes. 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. |
| تدمد: | 2214-7500 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::14832b7cdf9942079952c6c70ad2ff80 https://doi.org/10.1016/j.toxrep.2020.12.019 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....14832b7cdf9942079952c6c70ad2ff80 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22147500 |
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