Species differences in phenobarbital-mediated UGT gene induction in rat and human liver microtissues

Plummer, Simon; Beaumont, Bobby; Elcombe, Matthew; Wallace, Stephanie Jean; Wright, Jayne; McInnes, Elizabeth F.; Currie, Richard A.; Cowie, David E.

doi:10.1016/j.toxrep.2020.12.019

Cited by 13 publications

(14 citation statements)

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“…There is both overlap within a species and variability between species for thyroid hormone drug metabolizing enzymes and transporters, and orthologs do not always exist or recognize the same substrates (Shiratani et al, 2008;Van Groen et al, 2021). In the case of humans, transport and glucuronidation of thyroid hormone in vitro has been demonstrated by many OATPs and UGT enzymes (Tong et al, 2007;Meech et al, 2019;Plummer et al, 2021), and transporter expression can vary widely among individuals and populations (Amacher, 2016). Further, whereas regulation of enzymes and transporters by nuclear receptors occurs across species, the expression response in liver may vary among species.…”

Section: Current Hypothesis Gaps and Future Considerationsmentioning

confidence: 99%

“…In particular, this is true for regulation by CAR and PXR, where there are distinct differences in the amino acid sequences of the ligand-binding domains among rodents, rabbits, and humans (Wang et al, 2012;Amacher, 2016;Hakkola et al, 2020;Hammer et al, 2021) that result in differences in ligand preferences among species. Recently, using CAR response element sequence analysis of UGT promoters, it was found that human UGT promoters contained a higher proportion of consensus CAR response elements compared to the rat homologs, and there were differences in the UGT homologs that were induced in rat versus human 3D microtissues (Plummer et al, 2021).…”

Section: Current Hypothesis Gaps and Future Considerationsmentioning

confidence: 99%

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Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats

Vansell

2022

Drug Metabolism and Disposition

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Increased disposition of thyroid hormones is a way that xenobiotics may alter thyroid homeostasis and in rats, produce thyroid follicular adenoma/carcinoma. This capacity is historically attributed to induction of T4 glucuronidation by UGT enzymes, and cytochrome P450 induction is often a surrogate. However, gaps exist in correlating the effectiveness of certain chemical inducers at increasing T4 glucuronidation with decreases in systemic T4 and resulting increases in TSH. With the identification of other key inducible drug processing genes and proteins involved in hepatic disposition of thyroid hormones, including uptake (eg, Oatps) and efflux (eg, Mrps) transporters, data exist that support transporters as additional targets sites of induction. These data are reviewed herein and indicate an increase in hepatic uptake of thyroid hormones, as well as increased biliary excretion of iodothyronine conjugates, represent critical activities that differentiate inducer effectiveness in disrupting thyroid hormones in rats. Increased membrane transport of thyroid hormones, likely in conjunction with induced glucuronidation of thyroid hormone (T3 more relevant than T4), provide a better indication of thyroid disrupting potential than consideration of UGT induction alone. Because coordinate regulation of these targets is inconsistent among inducers belonging to various classes and among species, and there are disparities between in vitro assays and in vivo responses, further work is required to identify specific and relevant inducible thyroid hormone uptake transporters. Data from Mrp2-null animals has contributed key information, yet the contributions of efflux transport (canalicular and basolateral) to the mechanism of individual, effective inducers also requires further study.

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Section: Current Hypothesis Gaps and Future Considerationsmentioning

confidence: 99%

Section: Current Hypothesis Gaps and Future Considerationsmentioning

confidence: 99%

Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats

Vansell

2022

Drug Metabolism and Disposition

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“…There is substantial literature affirming that PB and PB-like compounds; i.e., showing the same behaviour despite no evident structural relationship with PB or each other [ 26 ], induce human and rodent DMEs, and primarily CYP2B. However, species differences in the pattern of induction have been reported as well [ 9 , 15 , 27 , 28 , 29 ]. On a comparative basis, and especially looking at veterinary species, few data about the PB-dependent up-regulation of hepatic CYPs are actually available for pigs [ 30 , 31 , 32 ], sheep [ 33 ], rabbit [ 34 ], chicken [ 35 , 36 ], or dog [ 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization

Cantiello

Carletti

Giantin

et al. 2022

IJMS

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In cattle, phenobarbital (PB) upregulates target drug-metabolizing enzyme (DME) mRNA levels. However, few data about PB’s post-transcriptional effects are actually available. This work provides the first, and an almost complete, characterization of PB-dependent changes in DME catalytic activities in bovine liver using common probe substrates and confirmatory immunoblotting investigations. As expected, PB increased the total cytochrome P450 (CYP) content and the extent of metyrapone binding; moreover, an augmentation of protein amounts and related enzyme activities was observed for known PB targets such as CYP2B, 2C, and 3A, but also CYP2E1. However, contradictory results were obtained for CYP1A, while a decreased catalytic activity was observed for flavin-containing monooxygenases 1 and 3. The barbiturate had no effect on the chosen hydrolytic and conjugative DMEs. For the first time, we also measured the 26S proteasome activity, and the increase observed in PB-treated cattle would suggest this post-translational event might contribute to cattle DME regulation. Overall, this study increased the knowledge of cattle hepatic drug metabolism, and further confirmed the presence of species differences in DME expression and activity between cattle, humans, and rodents. This reinforced the need for an extensive characterization and understanding of comparative molecular mechanisms involved in expression, regulation, and function of DMEs.

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“…11,12 In addition, phenobarbital also induces CYP1A2, CYP2B1, CYP2B2, CYP2B6, CYP2C9, UGT1A4, UGT1A8, and UGT1A9. 13,14 Patients with cerebral malaria with polymorphic CYP2C19 genotypes (altered phenobarbital clearance) who receive concurrent treatment with quinine are, therefore, at risk of inadequate or toxic therapeutic drug concentrations as a result of metabolic drug interactions. In addition, quinine is a narrow therapeutic drug (therapeutic range 10-20 mg L −1 , therapeutic index 2).…”

Section: Introductionmentioning

confidence: 99%

“…The activities of both CYP3A4 and UGT1A1 enzymes are induced by phenobarbital 11,12 . In addition, phenobarbital also induces CYP1A2, CYP2B1, CYP2B2, CYP2B6, CYP2C9, UGT1A4, UGT1A8, and UGT1A9 13,14 . Patients with cerebral malaria with polymorphic CYP2C19 genotypes (altered phenobarbital clearance) who receive concurrent treatment with quinine are, therefore, at risk of inadequate or toxic therapeutic drug concentrations as a result of metabolic drug interactions.…”

Section: Introductionmentioning

confidence: 99%

Physiologically based pharmacokinetic modeling for dose optimization of quinine–phenobarbital coadministration in patients with cerebral malaria

Saeheng

Rajoli

Siccardi

et al. 2021

CPT Pharmacom & Syst Pharma

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Species differences in phenobarbital-mediated UGT gene induction in rat and human liver microtissues

Cited by 13 publications

References 29 publications

Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats

Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats

Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization

Physiologically based pharmacokinetic modeling for dose optimization of quinine–phenobarbital coadministration in patients with cerebral malaria

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