UGT1A8

Last update 08 May 2025

Basic Info

Synonyms

GNT1, UDP glucuronosyltransferase family 1 member A8, UDP-glucuronosyltransferase 1-8

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Introduction

UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:15472229, PubMed:16595710, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:18719240, PubMed:19545173, PubMed:23288867, PubMed:21422672). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15472229, PubMed:16595710, PubMed:23288867). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens and estrogens (PubMed:15472229, PubMed:16595710, PubMed:18719240, PubMed:23288867). Produces dihydrotestosterone (DHT) diglucuronide from the DHT after two subsequent glucoronidation steps (PubMed:16595710). Involved in the glucuronidation of the phytochemical ferulic acid at the phenolic or the carboxylic acid group (PubMed:21422672). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212). Lacks UGT glucuronidation activity but acts as a negative regulator of isoform 1.

100 Clinical Results associated with UGT1A8

100 Translational Medicine associated with UGT1A8

0 Patents (Medical) associated with UGT1A8

278

Literatures (Medical) associated with UGT1A8

01 Mar 2025·Forensic Science International: Genetics

Tramadol-related fatalities: Metabolic ratios & SNPs/INDELs belonging to UGT1A8, UGT2B7, ABCC2, and SLC22A1

Article

Author: Aly, Sanaa M ; Gaulier, Jean-Michel ; Hennart, Benjamin ; Sabaouni, Naoual ; Allorge, Delphine

Genetic polymorphism can cause variation in tramadol (TR) pharmacokinetic characteristics and the expected clinical response. In forensic toxicology, the data about parent and metabolite concentrations (MRs; metabolic ratios) could facilitate to determine the cause of death and to assess time between drug intake and death. In this study, the aim was to investigate if UGT1A8, UGT2B7, ABCC2, and SLC22A1 genotyping can facilitate interpretation by investigating the frequency of UGT1A8, UGT2B7, ABCC2, and SLC22A1 genotypes in forensic autopsy cases positive for TR and to assess whether there is a correlation between these genetic variants and MRs. Cases positive for TR (n = 48) were genotyped by HaloPlex Target Enrichment system for UGT1A8, UGT2B7, ABCC2, and SLC22A1 sequencing, in order to identify single nucleotide polymorphisms (SNPs) and/or insertion deletion (INDELs). In addition to, the concentrations of TR and its metabolites (M1 & M2) were determined by LC-MS/MS. Cases were categorized by cause of death. The investigated SNPs/INDELs were not overrepresented in any group. We found significant correlations between several loci (12 out of 73) in UGT1A8, ABCC2, and SLC22A1 genes and MRs (M2/M1, TR/M2, and TR/M1) in post-mortem TR cases. These results indicate these polymorphisms in the 4 investigated genes might influence TR pharmacokinetics leading to an unsatisfactory therapeutic effect or increasing the risk of toxicity. However, these findings should be supported in future studies with larger groups of cases.

01 Feb 2025·Psychoneuroendocrinology

Genetic variants in COMT and ESR1 genes shape treatment response to raloxifene in schizophrenia-spectrum disorders

Article

Author: Morris, Kim ; de Boer, Janna N ; Sommer, Iris E C ; Rossell, Susan ; Brand, Bodyl A ; Boer, Anne Jetske ; Bozaoglu, Kiymet

BACKGROUND/OBJECTIVERaloxifene, a selective estrogen receptor modulator (SERM), may improve symptoms and cognition in schizophrenia spectrum disorders (SSD). Studies have shown inconsistent efficacy, especially in men with SSD. We assessed whether single nucleotide polymorphisms (SNPs) on genes involved in the pharmacodynamics (ESR1 and COMT) and pharmacokinetics (UGT1A8) of raloxifene can explain the heterogeneous treatment response to raloxifene augmentation in patients with SSD.METHODSWe used a subsample of the participants of a previously published randomized controlled trial (RCT) on the effects of 12-week raloxifene augmentation on symptom severity in SSD. The subsample consisted of 83 participants (28 % female), of which 40 were randomized to receive raloxifene 120 mg/day and 43 to placebo. Saliva samples for DNA-analysis were collected at baseline, symptom severity was measured with the Positive and Negative Syndrome Scale (PANSS). Participants were genotyped for two SNPs on ESR1, one on UGT1A8, and four on COMT using the Agena MassArray system. Linear mixed-effect models were used to assess the effect of treatment-by-genotype as the primary analysis and treatment-by-genotype-by-sex as a secondary analysis.RESULTSWe found interactions of treatment-by-genotype for ESR1 rs2234693 (χ² = 6.32, p < 0.05), and COMT rs4818 (χ² = 4.08, p < 0.05), indicating that for these polymorphisms, the effect of raloxifene differed per genotype. Pairwise comparisons revealed a beneficial effect of raloxifene on general symptom severity in participants with ESR1 rs2234693 TT genotype but not CT and CC genotypes (LSM -3.19 [95 % CI -6.38-0.00]; p = 0.050). Furthermore, mean change in positive symptom severity was greater with raloxifene in participants with COMT rs4818 CG genotype but not CC genotype compared to placebo (LSM -2.18 [-3.93 to -0.43]; p = 0.016). Secondary sex-specific analysis indicated an interaction effect of treatment-by-genotype-by-sex for COMT rs737865 on total (χ² = 10.90, p < 0.05) and negative symptom severity (χ² = 11.99, p < 0.05). In men, genotype CT but not TT was associated with beneficial effects of raloxifene on total symptoms (LSM -5.46 [-10.43 to -0.48]; p = 0.032), whereas in women, genotype TT but not CT was associated with a beneficial effect of raloxifene on negative symptoms (LSM -7.80 [-12.70 to -2.89]; p = 0.005).CONCLUSIONOur results suggest that treatment response to raloxifene may depend on ESR1 and COMT gene variants, while UGT1A8 SNP variation did not affect treatment response. These findings provide evidence that genetic variants may explain the heterogeneous response to raloxifene augmentation in SSD, suggesting that raloxifene may have beneficial effects in genetic subgroups of SSD patients. Our findings warrant further research on the pharmacogenetic effects of raloxifene in SSD.

01 Sep 2024·European Journal of Drug Metabolism and Pharmacokinetics

In Vitro Ciclopirox Glucuronidation in Liver Microsomes from Humans and Various Experimental Animals

Article

Author: Huang, Zhu ; Zhang, Feng ; Xiao, Ling ; Zhu, Liangliang ; Ge, Guangbo ; Li, Wenjing ; Xue, Yufan ; Li, Wenjuan

BACKGROUND AND OBJECTIVECiclopirox is a widely used antifungal drug, redisposition of which has drawn increasing attentions due to multiple promising activities. The drug undergoes extensive glucuronidation, which acts as a major obstacle in the ongoing novel application and still remains poorly understood. The current study aims to phenotype ciclopirox glucuronidation pathway and as well to decipher the related species differences.METHODSCiclopirox glucuronidation was investigated in liver microsomes from humans (HLM) and various experimental animals. Assays with recombinant uridine diphosphate glucuronosyltransferases (UGTs), enzyme kinetic analyses and selective inhibitors were used to determine the role of individual UGTs in ciclopirox glucuronidation.RESULTSHLM is highly active in ciclopirox glucuronidation with Michaelis-Menten constant (K_m), maximum velocity (V_max), and intrinsic clearance (CL_int) values of 139 μM, 7.89 nmol/min/mg, and 56 μL/min/mg, respectively. UGT1A9 displays by far the highest activity, whereas several other isoforms (UGT1A6, UGT1A7, and UGT1A8) catalyze formation of traced glucuronides. Further kinetic analysis demonstrates that UGT1A9 has a closed K_m value (167 μM) to HLM. UGT1A9 selective inhibitor (magnolol) can potently inhibit ciclopirox glucuronidation in HLM with the IC₅₀ value of 0.12 μM. The reaction displays remarkable differences across liver microsomes from mice, rats, cynomolgus monkey, minipig, and beagle dog, with the CL_int values in the range of 26-369 μL/min/mg. In addition, ciclopirox glucuronidation activities of experimental animals' liver microsomes were less sensitive to magnolol than that of HLM.CONCLUSIONSCiclopirox glucuronidation displays remarkable species differences with UGT1A9 as a dominant contributor in humans. It is suggested that the pharmacological or toxicological effects of ciclopirox may be UGT1A9 and species dependent.

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UGT1A8

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