尿苷二磷酸葡萄糖醛酸转移酶的转录调节与疾病相关性的研究进展

葡萄糖醛酸结合反应是体内重要的Ⅱ相代谢途径,主要由尿苷二磷酸葡萄糖醛酸转移酶（ UGT ）催化。尿苷二磷酸葡萄糖醛酸转移酶能参与多种内源性物质如胆红素、胆汁酸、甲状腺激素等的代谢,也能参与多种药物如阿片类镇痛药、非甾体抗炎药等药物的代谢,在代谢解毒方面起着重要作用。近年来对尿苷二磷酸葡萄糖醛酸转移酶的研究越来越深入,尿苷二磷酸葡萄糖醛酸转移酶与不同疾病的研究受到普遍关注。本文就转录因子介导的尿苷二磷酸葡萄糖醛酸转移酶的分子调节机制及其与不同疾病的相关性研究进行综述。     

尿苷二磷酸葡醛酸转移酶介导的胆汁酸代谢过程及其内源和外源影响因素研究进展

尿苷二磷酸葡萄糖醛酸转移酶(UDP-glucuronosyltransferases, UGTs)作为人体中一种非常重要的II相代谢酶,不仅参与外源性化合物代谢清除,也在胆汁酸等内源性物质的代谢调控中扮演重要角色。解析尿苷二磷酸葡萄糖醛酸转移酶介导的胆汁酸代谢过程及其内源和外源影响因素有助于增强对相关疾病的治疗和预防。尿苷二磷酸葡萄糖醛酸转移酶对胆汁酸代谢调控作用受到多种内源性和外源性因素影响。本文将重点探讨核受体、遗传因素、外源化合物及肝脏相关疾病等因素对UGT酶作用的影响,讨论体内潜在的胆汁酸动态平衡干预机制。     

尿苷二磷酸葡萄糖醛酸转移酶介导的药物相互作用的研究进展

葡萄糖醛酸结合反应是生物体内重要的Ⅱ相代谢途径,由尿苷二磷酸葡萄糖醛酸转移酶(UGT)催化完成,是多种内源性物质和外源性化合物清除与解毒的机制。在新药研发过程中,研究UGT介导的药物代谢以及评估潜在的药物相互作用是非常重要的,吸引了很多研究人员的关注。但目前的研究偏重于由细胞色素P450酶(CYP450)介导的药物相互作用,对UGT的关注相对较少。鉴于UGT在药物代谢中的重要性,有必要对其导致的药物相互作用进行更深入的研究。本文综述了由UGT的抑制引起的药物相互作用的相关研究进展。     

尿苷二磷酸葡醛酸转移酶的研究进展

尿苷二磷酸葡醛酸转移酶(UGT)是体内最重要的Ⅱ相代谢酶,它可以参与许多内源性物质如胆红素、甾体激素、甲状腺激素、胆汁酸和脂溶性维生素等的代谢,在许多药物如阿片类药物、镇痛药、非甾体抗炎药和抗惊厥药等的代谢中也发挥着重要的作用。UGT在药物的吸收、分布、代谢和排泄中发挥重要作用。研究UGT特别是其基因多态性及其介导的药物-药物相互作用不仅可以指导临床用药,也可以揭示内源性物质代谢紊乱的机制。本文就UGT的分类、组织分布、对药物吸收的影响、基因多态性及其所介导的药物-药物相互作用进行综述。     

尿苷二磷酸葡萄糖醛酸转移酶的调控及其介导的中药-药物相互作用研究进展

尿苷二磷酸葡萄糖醛酸转移酶（UGT）催化的葡萄糖醛酸化反应是的是Ⅱ相代谢中重要的代谢反应之一,对于维持内源性化合物如胆红素、胆汁酸的动态平衡和药物、致癌物等外源性化合物的处置过程起着至关重要的作用。UGTs的表达和酶活性受多维机制的调控。深入研究其调控网络以及UGT介导的相关中药-药物相互作用,对于临床更安全、有效的使用中药提供了指导。因此,本文总结了尿苷二磷酸葡萄糖醛酸转移酶的转录前、转录水平、翻译后修饰等分子调节机制,以及由UGT介导的中药-药物相互作用相关的研究进展。     

尿苷二磷酸葡萄糖醛酸转移酶基因多态性对药物代谢影响的研究进展

由尿苷二磷酸葡萄糖醛酸转移酶(UDP-glucuronosyltransferase,UGT)催化完成的葡萄糖醛酸结合反应是生物体内重要的Ⅱ相代谢途径,它与毒性或活性物质结合形成葡萄糖醛酸苷,将内源性、外源性化合物通过胆汁或肾脏排出体外。UGT是一个超家族酶,因主要利用UDP-尿苷二磷酸葡糖醛酸为糖基供体而得名。人类UCT广泛分布于体内的各种组织,包括肾、脑、皮肤、肠、脾、胸腺、心脏等,其中以     

胆红素代谢酶UGT1A1介导的中药不良反应研究进展

尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1）是哺乳动物体内分布的一种重要的Ⅱ相代谢酶,其不仅介导了大量临床药物、毒物的代谢清除,还是机体参与内源性毒性物质胆红素代谢清除的唯一代谢酶。药物或食品中的化学成分对UGT1A1的强烈抑制会引发多种不良反应,如药物/草药-药物相互作用、高胆红素血症、肝功能异常及神经毒性等。近年来,研究发现许多草药提取物及其化学成分可通过强效抑制UGT1A1引发药物-草药相互作用等不良反应。结合药物代谢及药物毒理学相关领域的新近研究进展,系统总结了UGT1A1抑制剂筛选与评价常用方法,以及中草药化学成分对UGT1A1抑制作用的研究进展。上述信息对于临床安全合理的使用中草药,尤其是在中西药联用或中药方剂使用过程中尽可能避免因UGT1A1抑制引发的不良反应,具有重要指导意义。     

肝损状态下尿苷二磷酸葡萄糖醛酸转移酶研究进展

肝脏是人体内最重要的代谢器官,包含绝大部分的Ⅰ相和Ⅱ相代谢酶,在内源性和外源性物质的代谢解毒方面起着重要的作用.参与葡萄糖醛酸代谢的尿苷二磷酸葡萄糖醛酸转移酶(UGT)是Ⅱ相代谢中最重要的酶,与常见的CYP450酶相比,研究相对滞后,尤其在肝损伤状态下UGT的相关研究仍处于探索阶段.本文参考最新UGT的研究成果,综述了UGT分子生物学目前研究的概况、肝脏分布及其与肝脏疾病的关系;总结了几种不同诱因的肝损伤病理状态UGT表达和葡萄糖醛酸代谢的变化情况并且深入探讨了相关机制,旨在为药物的肝脏代谢尤其是在肝损状态下葡萄糖醛酸结合消除研究提供一定的参考依据,为肝脏疾病患者的临床合理用药提供指导.     

人尿苷二磷酸葡萄糖醛酸转移酶基因多态性与相关疾病易感性

尿苷二磷酸葡萄糖醛酸转移酶(UGT)是体内重要的药物代谢Ⅱ相酶,具有明显的基因多态性。评价基因多态性对疾病易感性影响的重要性,建立基因多态性数据库并进行致病基因-疾病易感性的种群研究具有深远意义。本文拟就人UGT基因多态性及相关疾病易感性进行简述。     

UGT1A4基因多态性对儿童拉莫三嗪药动学影响的研究进展

UGT1A4是尿苷二磷酸葡萄糖醛酸基转移酶(UGT)重要的一种亚型,参与生物体内Ⅱ相生物转化,代谢大量的外源性和内源性物质,研究发现UGT1A4基因多态性是多种药物体外代谢速率存在差异的重要原因之一。拉莫三嗪作为一种新型的抗癫痫药物,已广泛用于癫痫患儿的治疗,它主要通过UGT1A4进行代谢,故UGT1A4基因多态性可能会对其代谢产生影响。本文就UGT1A4基因多态性对儿童拉莫三嗪药物动学影响的研究现状作一综述。     

The inhibition of UDP-glucuronosyltransferases (UGTs) by tetraiodothyronine (T4) and triiodothyronine (T3)

1.?UDP-glucuronosyltransferases (UGTs) are important drug-metabolizing enzymes (DMEs) catalyzing the glucuronidation elimination of various xenobiotics and endogenous substances. Endogenous substances are important regulators for the activity of various UGT isoforms. Triiodothyronine (T3) and thyroxine (T4) are important thyroid hormones essential for normal cellular differentiation and growth. The present study aims to elucidate the inhibition behavior of T3 and T4 on the activity of UGT isoforms.

2.?In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to screen the inhibition potential of T3 and T4 on the activity of various UGT isoforms. Initial screening results showed that T4 exerted stronger inhibition potential than T3 on the activity of various UGT isoforms at 100?μM. Inhibition kinetics was determined for the inhibition of T4 on the representative UGT isoforms, including UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7. The results showed that T4 competitively inhibited the activity of UGT1A1, -1A3, -1A7, 1A10 and -2B7, and noncompetitively inhibited the activity of UGT1A8. The inhibition kinetic parameters were calculated to be 1.5, 2.4, 11, 9.6, 4.8 and 3.0?μM for UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7, respectively. In silico docking method was employed to demonstrate why T4 exerted stronger inhibition than T3 towards UGT1A1. Stronger hydrogen bonds and hydrophobic interaction between T4 and activity cavity of UGT1A1 than T3 contributed to stronger inhibition of T4 towards UGT1A1.

3.?In conclusion, more clinical monitoring should be given for the patients with the elevation of T4 level due to stronger inhibition of UGT isoforms-catalyzed metabolism of drugs or endogenous substances by T4.     

The effects of UDP-sugars,UDP and Mg2+on uridine diphosphate glucuronosyltransferase activity in human liver microsomes

1. The UDP-glucuronosyltransferase (UGT) enzymes are important in the metabolism, elimination and detoxification of many xenobiotics and endogenous compounds. As extrapolation of in vitro kinetics of drug metabolizing enzymes to predict in vivo clearance rates becomes more sophisticated, it is important to ensure proper optimization of enzyme assays. The luminal location of the enzyme active site (i.e. latency), and the complexity of UGT kinetics, results in consistent under-prediction of clearance of drugs metabolized by glucuronidation.

2. We examined inhibition of UGT activity in alamethicin-disrupted human liver microsomes (HLM) by uridine diphosphate (UDP), a UGT reaction product, and its reversal by Mg²⁺ ions. We also determined whether UDP-sugars other than the co-substrate UDP-glucuronic acid (UDP-GlcA) affected glucuronidation.

3. We show that other UDP-sugars do not significantly influence glucuronidation. We also demonstrate that UDP inhibits HLM UGT activity and that this is reversed by including Mg²⁺ in the assay. The Mg²⁺ effect can be offset using EDTA, and is dependent on the concentration of UDP-GlcA in the assay.

4. We propose that formation of a Mg²⁺–UDP complex prevents UDP from affecting the enzyme. Our results suggest that 5?mM UDP-GlcA and 10?mM Mg²⁺ be used for UGT assays in fully disrupted HLM.     

Glucuronidation: driving factors and their impact on glucuronide disposition

Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.     

Inhibitory potential of chlormadinone acetate (CMA) on five important UDP-glucuronosyltransferases in human liver

Chlormadinone acetate (CMA), a derivative of 17-a-hydroxyprogesterone, has been widely used as an orally effective progestogen in hormone replacement therapy (HRT). Glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs) is one of the major steps responsible for the metabolism of many drugs, environmental chemicals and endogenous compounds. Pharmacokinetic behaviours of drugs could be altered by inhibition of these UGT isoforms, and the search for drugs that potentially inhibit these UGT isoforms is very significant from a clinical point of view. In the present study, inhibition of five important UGT isoforms in human liver (UGT1A1, 1A3, 1A6, 1A9 and 2B7) by CMA was investigated using 4-MU as nonspecific substrate and recombinant UGT isoforms as enzyme sources. The results showed that CMA exhibited inhibitory effects on UGT1A3 (IC50 = 8.6 +/- 1.4 microM) and UGT2B7 (IC50 = 14.2 +/- 3.8 microM), with other UGT isoforms negligibly influenced. Lineweaver-Burk and Dixon plots showed that CMA noncompetitively inhibited UGT1A3 and UGT2B7. The Ki value was calculated to be 36.9 microM and 4.1 microM for UGT1A3 and UGT2B7, respectively. Considering that UGT1A3 and UGT2B7 are involved in the metabolism of many drugs, special attentions should be paid when CMA was co-administered with the drugs which mainly underwent UGT1A3, 2B7-mediated metabolism.     

Polymorphism of UDP-glucuronosyltransferase and drug metabolism

UDP-glucuronosyltransferase is a group of catabolic enzymes involved in the detoxification and excretion of many xenobiotic and endogeneous substances in intrahepatic and extrahepatic tissues. The group consists of two subfamilies, UGT1 and UGT2. UGT1 consists of 5 exons and has a unique gene structure. There are thirteen exon 1s from UGT1A1 to UGT1A13P, and exon 2 to exon 5 are used in common for all mRNAs expressed from the gene. Each isoform of UGT1 results from differential splicing of exon1s to common exon 2-5, and has an unique spectrum of substrate specificity. In contrast, the genes of the UGT2 family consist of 6 exons, and all the enzymes have an individual set of exon 1 to exon 6. In UGT1 there are no reports of polymorphism in the common exons, although a number of polymorphisms have been reported for exon 1s. The mutations of UGT1A1 cause hereditary unconjugated hyperbilirubinemias: Crigler-Najjar syndrome type I, type II and Gilbert syndrome. UGT1A1 has two major polymorphisms--a missense mutation of G71R and an insertion mutation of TATA box. Prevalence of Gilbert syndrome is attributed to these polymorphisms. Since UGT1A1 metabolizes not only bilirubin but also hormones and drugs, the mutations could be involved in carcinogenesis and adverse drug reactions. Recent studies also revealed a widespread presence of diverse polymorphisms in other isoforms of UGT1 as well as the UGT2 family, including UGT1A6, UGTG1A7, UGT1A8, UGT1A10, UGT2B4, UGT2B7 and UGT2B15. The incidences and types of the polymorphisms for these enzymes are quite different in region and ethnic groups. Understanding of these polymorphisms is essential for the prevention of adverse effects of a considerable number of drugs and to predict cancer risks.