UDP-glucuronosyltransferases (UGTs) and their related metabolic cross-talk with internal homeostasis: A systematic review of UGT isoforms for precision medicine

Yang, Na; Sun, Runbin; Liao, Xiaoying; Aa, Jiye; Wang, Guangji

doi:10.1016/j.phrs.2017.05.001

Cited by 89 publications

(61 citation statements)

References 177 publications

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“…Results of this study suggest that the mouse model could possibly be suitable for such studies. Nevertheless, caution should be taken when extrapolating data from mice to humans due to the lack of sufficient knowledge about species differences in functions, expression, and tissue distribution of individual UGT/Ugt isoforms between humans and mice (Yang et al, 2017). Indeed, we showed in this study that the K m values of NBUP-G formation by Ugts in mouse liver were six to seven times lower than the K m of human UGTs reported in a previous study (Chang and Moody, 2009).…”

Section: Pk Parametercontrasting

confidence: 59%

Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation

et al. 2017

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Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) that is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP's analgesic activity and 10 times BUP's respiratory depression effect. To optimize BUP's dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and nonpregnant mice by administering the same amount of NBUP through retro-orbital injection. We demonstrated that the systemic clearance (CL) of NBUP in pregnant mice increased ∼2.5-fold compared with nonpregnant mice. Intrinsic CL of NBUP by glucuronidation in mouse liver microsomes from pregnant mice was ∼2 times greater than that from nonpregnant mice. Targeted liquid chromatography tandem-mass spectrometry proteomics quantification revealed that hepatic Ugt1a1 and Ugt2b1 protein levels in the same amount of total liver membrane proteins were significantly increased by ∼50% in pregnant mice versus nonpregnant mice. After scaling to the whole liver with consideration of the increase in liver protein content and liver weight, we found that the amounts of Ugt1a1, Ugt1a10, Ugt2b1, and Ugt2b35 protein in the whole liver of pregnant mice were significantly increased ∼2-fold compared with nonpregnant mice. These data suggest that the increased systemic CL of NBUP in pregnant mice is likely caused by an induction of hepatic Ugt expression and activity. The data provide a basis for further mechanistic analysis of pregnancy-induced changes in the disposition of NBUP and drugs that are predominately and extensively metabolized by Ugts.

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Section: Pk Parametercontrasting

confidence: 59%

Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation

et al. 2017

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“…Moreover, ten UDP-Glucuronosyltransferases in the pentose and glucoronate interconversions pathway (ko00040) and ascorbate and aldarate metabolism pathway (ko00053) (ugt1a1, ugt1a2, ugt1ab, ugt1a7, ugt1b2, ugt2a2, ugt2a4, ugt2b3, ugt5b1, ugt5b4) were all dramatically decreased. These UGTs are mainly expressed in liver, which are phase II biotransformation enzymes that regulate the glucuronidation reaction [29]. Taken together, these data suggested that GCGR is essential to maintain carbohydrate metabolism and its deficiency results in the disorder of carbohydrate metabolism.…”

Section: Gcgr Regulates Carbohydrate Metabolismmentioning

confidence: 84%

Global Transcriptomic Analysis of Zebrafish Glucagon Receptor Mutant Reveals Its Regulated Metabolic Network

Kang

Jia

et al. 2020

IJMS

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The glucagon receptor (GCGR) is a G-protein-coupled receptor (GPCR) that mediates the activity of glucagon. Disruption of GCGR results in many metabolic alterations, including increased glucose tolerance, decreased adiposity, hypoglycemia, and pancreatic α-cell hyperplasia. To better understand the global transcriptomic changes resulting from GCGR deficiency, we performed whole-organism RNA sequencing analysis in wild type and gcgr-deficient zebrafish. We found that the expression of 1645 genes changes more than two-fold among mutants. Most of these genes are related to metabolism of carbohydrates, lipids, and amino acids. Genes related to fatty acid β-oxidation, amino acid catabolism, and ureagenesis are often downregulated. Among gcrgr-deficient zebrafish, we experimentally confirmed increases in lipid accumulation in the liver and whole-body glucose uptake, as well as a modest decrease in total amino acid content. These results provide new information about the global metabolic network that GCGR signaling regulates in addition to a better understanding of the receptor’s physiological functions.

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“…The inconsistence between our result and Sun’ findings might be due to the high similarity of UGT isoforms in terms of gene and protein structure. A considerable number of substrates are glucuronidated by multiple UGT isoforms because several isoforms may contribute similarly to the metabolism of some specific substance at the same time, and sometimes it is difficult to identify the predominant UGT isoform responsible for the glucuronidation reaction . For instance, paracetamol glucuronidation was catalysed by UGT1A1, as well as UGT1A6, UGT1A9 and UGT2B15 .…”

Section: Discussionmentioning

confidence: 99%

Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole‐induced liver injury

Jin

Fan

et al. 2019

Basic Clin Pharma Tox

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Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug‐induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug‐metabolizing enzymes and drug transporters have been associated with drug‐induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug‐metabolizing enzymes and drug transporters to the MMI‐DILI. A total of 44 GD patients with MMI‐DILI and 118 GD patients without MMI‐DILI development were included in the study. Thirty‐three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI‐DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI‐DILI cases than that in the control group (OR = 2.21, 95% CI = 1.11‐4.39, P = 0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR = 0.52, 95% CI = 0.29‐0.93, P = 0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI‐DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI‐induced hepatotoxicity.

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UDP-glucuronosyltransferases (UGTs) and their related metabolic cross-talk with internal homeostasis: A systematic review of UGT isoforms for precision medicine

Cited by 89 publications

References 177 publications

Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation

Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation

Global Transcriptomic Analysis of Zebrafish Glucagon Receptor Mutant Reveals Its Regulated Metabolic Network

Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole‐induced liver injury

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