Disease relevance of Ugt1a1

• The Gunn rat is a mutant strain of Wistar rat which has unconjugated hyperbilirubinemia as a result of the absence of hepatic UDP-glucuronosyltransferase (UDPGT) activity toward bilirubin [1].
• These findings indicate a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinotecan toxicity [2].
• In behavioural experiments, the B1 antagonist desArg10HOE140, administered by either intrathecal or systemic routes, attenuated Freund's complete adjuvant-induced mechanical hyperalgesia in the inflamed paw, but did not affect mechanical allodynia [3].
• Twenty-four hours after injection of Freund's complete adjuvant into one hindpaw, there was a significant increase in B1 protein expression (measured by immunohistochemistry) in both ipsilateral and contralateral dorsal root ganglion neurones, whereas axotomy resulted in reduction of B1 protein in ipsilateral dorsal root ganglia [3].
• Overall, these data suggest that the loss in crystallin mRNAs in response to the development of galactose cataracts follows this order of decline: gamma greater than alpha B greater than alpha A greater than beta B1 [4].

High impact information on Ugt1a1

• At 24 d after ablation, at which time sclerosis is not evident, endothelial cells, particularly in the dilated capillaries at the vascular pole, expressed angiotensinogen and TGF-beta 1 mRNAs, as well as fibronectin and laminin B1 RNA transcripts [5].
• All receptor blockade inhibited angiotensinogen, TGF-beta 1, fibronectin, and laminin B1 mRNA expression by the endothelium [5].
• Isoforms II (elution pH 8.4), III (elution pH 8.0), and IV (elution pH 7.8) from Gunn rats had normal UDPGT activities, except that Isoform IV was inactive toward bilirubin [6].
• UDPGT isoform I (elution pH 8.7) from Wistar (RHA) and Gunn rats was active toward 4-nitrophenol [6].
• Gunn rats are a mutant strain of Wistar rats that have unconjugated hyperbilirubinemia due to absence of hepatic uridine diphosphate-glucuronosyltransferase (UDPGT; EC. 2.4.1.17) activity toward bilirubin [6].

Chemical compound and disease context of Ugt1a1

• Activation of either B1 or B2 bradykinin receptors by kinins released from damaged tissues contributes to the development and maintenance of inflammatory hyperalgesia [3].
• 6 In summary, we have shown that in endotoxemia activation of B1 receptors causes coronary vasodilation via endothelial prostacyclin release [7].
• The synthesis and distribution of the kinin B1 and B2 receptors are modified in the hippocampus of rats submitted to pilocarpine model of epilepsy [8].
• In rats fed a vitamin A-balanced diet, a single injection of l-T3 (500 microg/kg body weight) increased UGT1A6 mRNA expression whereas this hormone decreased UGT1A1 mRNA expression [9].
• In contrast, the amounts of message for laminin B1 remain identical after 1 week and 4 weeks of cyclosporine administration, despite the development of fibrosis at 4 weeks [10].

Biological context of Ugt1a1

• We therefore made a cDNA library from MC-treated Gunn rat liver mRNA and isolated cDNA clones, using the 4-NP UDPGT cDNA as a probe [11].
• Three novel cDNAs were identified that had identical 3'-regions of 1362 base pairs containing a single-base deletion in the same position as that of the mutant 4NP-UDPGT cDNA [1].
• The PB-like inducers, 2,2',4,4',5, 5'-hexachlorobiphenyl (HCB) and 1,1-dichloro-2, 2-bis(p-chlorophenyl)ethane (o,p-DDD), proportionally induced the CYP2B1/2B2 and UDPGT genes and activated the plasmid (HCB = PB > DDD) [12].
• These results show that chemoprevention by ANIT against PhIP-induced rat mammary carcinogenesis can be explained by a dual action mechanism, i.e. a reduction in metabolic activation by hepatic CYP1A2 and an enhancement of detoxification by 4-NP UDPGT [13].
• Mapping of rat bilirubin UDP-glucuronosyl-transferase gene (Ugt1a1) to chromosome region 9q35-->q36 [14].

Anatomical context of Ugt1a1

• The size of mRNA in Gunn rats was identical to that of the functionally mature UDPGT mRNA in Wistar rats, but the MC-inducible UDPGT protein was absent from homozygous Gunn rat microsomes [11].
• Hepatocytes exhibited a marked decline in UGT1A1 activity in the first 4 h of culturing (10% of initial activity) and the recovery took 72 h [15].
• On the other hand, UDPGT activity towards 4-nitrophenol (4-NP) was enhanced using liver microsomes prepared from rats pretreated with a combination of PhIP and ANIT as compared with those pretreated with PhIP or ANIT alone [13].
• The steady-state levels of mRNAs coding for two components of basement membranes, the alpha 1 chain of type IV collagen and the B1 chain of laminin, were measured in the kidneys of male CDF rats following the induction of diabetes with streptozotocin for periods of between 2 days and 28 weeks [16].
• It has been speculated that the B1 isoform might be involved in targeting to the plasma membrane [17].

Associations of Ugt1a1 with chemical compounds

• The Gunn rat is also deficient in UDPGT activities toward phenol substrates, and also toward digitoxigenin-monodigitoxiside [1].
• Among the isozymes expressed in rat hepatic microsomes, UGT1B1 (54 kDa) of bilirubin cluster was found to be a major form and minor forms were identified as UGT1A1 (53 kDa), UGT1B2 (56 kDa), and UGT1B5 (57 kDa) [18].
• Marked induction was detected in the cases of dexamethasone, clofibrate, and rifampicin treatments for 96 h both in enzyme activity (178, 176, and 168%) and in UGT1A1 protein level (362, 328, and 250%) [15].
• The rapid degradation of truncated UGT1A1 protein was inhibited partially but not completely by treating Gunn rat hepatocytes with proteasome inhibitors such as carbobenzoxy-Leu-Leu-leucinal and lactacystin [19].
• On the other hand, marked elevations of UDPGT activities toward p-nitrophenol (164-281% of control) were observed [20].

Regulatory relationships of Ugt1a1

• The effect of dicoumarol on glucuronidation of 3-OH-benzo(a)pyrene (BP) appears to be due to inhibition of UDPglucuronosyltransferase (UDPGT) and not to an inhibited DT-diaphorase (NAD(P)H:quinone oxidoreductase); to date the only enzyme known to be inhibited by dicoumarol [21].

Other interactions of Ugt1a1

• We administered these agrochemicals to the male rat and examined their effects on cytochrome P450 (P450), glutathione S-transferase (GST), UDP-glucuronosyltransferase (UDPGT), and NAD(P)H-quinone oxidoreductase 1 (NQO1)-related metabolism in the liver [20].
• UDP-glucuronosyltransferase (UGT1A1) is a critical enzyme in the elimination of bilirubin [15].
• Though supplementary vanadium had little or no influence on the contents of cytochrome P450 and b5 and activities of CYP2E1 and AHH in HNs and NNSP, it substantially elevated the UDPGT activity in both HNs and NNSP liver areas [22].
• These data are consistent with a role for NAT, CYP, and UDPGT in the biotransformation of BAT [23].
• The UGT1A6 gene (formerly known as UGT1*06 and UGT1A1) has been suggested to belong to the aryl hydrocarbon (Ah) gene battery, which consists of several genes encoding for drug-metabolising enzymes regulated by dioxin and other ligands of the Ah receptor [24].

Analytical, diagnostic and therapeutic context of Ugt1a1

• Pulse-chase experiments using primary cell cultures showed that the truncated UGT1A1 protein in Gunn rat hepatocytes was synthesized similarly to wild-type UGT1A1 protein in normal Wistar rat hepatocytes [19].
• The mRNA of UGT1A1, which is an isoform contributing to the glucuronidation of bilirubin, increased significantly in the liver and slightly in the kidney after hypophysectomy [25].
• A 1,763-bp cDNA probe (UGT1*0) specific for rat liver bilirubin UGT was used to localize the UGT1 complex locus (Ugt1a1) to chromosome region 9q35-->q36 by fluorescence in situ hybridization [14].
• Following 3,5, 3'-triiodo-L-thyronine (T3) stimulation in vivo, there is a gradual increase in the amount of UGT1A1 mRNA with maximum levels reached 24 h after treatment [26].
• METHODS: Using a RT-PCR/Southern blot approach allowing relative quantification of mRNA levels, ten different microdissected rat nephron segments were analyzed for the presence of the B1- and B2-receptor before and after endotoxin treatment to induce experimental inflammation [27].

References