ライフサイエンスコーパス: UGT1A1

1 UGT1A1 catalyzes the conjugation of bilirubin with glucu

2 UGT1A1 genotype and total bilirubin levels are strongly

3 UGT1A1 genotype did not influence clearance of TAS-103.

4 UGT1A1 genotypes were determined using reverse-transcrip

5 UGT1A1 protein level correlated strongly with both liver

6 UGT1A1 variants (-3279G>T, -3156G>A, promoter TA indel,

7 UGT1A1 was also induced in the human intestinal Caco-2 c

8 UGT1A1*28 genotype was not associated with grade 3 and 4

9 UGT1A1, the sole enzyme responsible for the metabolism o

10 omoter of the UDP-glucuronosyltransferase 1 (UGT1A1) gene has been shown to cause Gilbert syndrome, a

11 hosphoglucuronate glucuronosyltransferase-1 (UGT1A1) completely or partially abolish hepatic bilirubi

12 e uridine diphosphate glycosyltransferase 1 (UGT1A1) gene.

13 pression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the inability to metabolize bilirubin.

14 UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active meta

15 ion between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinote

16 In mammals, UDP-glucuronosyltransferase 1A1 (UGT1A1) is the sole enzyme responsible for bilirubin glu

17 UDP-glucuronosyltransferase 1A1 (UGT1A1) plays an important physiological role by contrib

18 ily through UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed glucuronidation.

19 osphate glucuronosyltransferase isoform 1A1 (UGT1A1).

20 A C127Y substitution abolished UGT1A1 activity, but not its dimerization.

21 ically significant DDIs when co-administered UGT1A1 or 2B17 substrates.

22 ibited potent competitive inhibition against UGT1A1 activity with a Ki of 0.5 muM.

23 rate for P-glycoprotein, CYP3A4, CYP3A5, and UGT1A1.

24 ned by ABCC1 1684T>C, ABCB1 IVS9 -44A>G, and UGT1A1*93 (P = .004).

25 limited to specific tissues, both GSTM1 and UGT1A1 are involved in the conjugation (and thus transpo

26 SWI/SNF target promoter templates (c-myc and UGT1A1), we observed hSWI/SNF-driven depletion of normal

27 genes in liver, including CYP3A, Oatp2, and UGT1A1.

28 ity, pharmacokinetics, pharmacodynamics, and UGT1A1 genotype.

29 Pharmacokinetic studies and UGT1A1 genotyping were performed.

30 etween the prevalence of severe toxicity and UGT1A1 genetic variation.

31 and UGT1A10 > UGT1A9 > UGT2B7 approximately UGT1A1 > UGT1A7 for (+)-BPD.

32 in protein and catalytic activity as well as UGT1A1 mRNA.

33 Because UGT1A1 in humans is responsible for 100% of the conjugat

34 No association between UGT1A1 genotype (n = 61) and toxicity or pharmacokinetic

35 To date, no significant association between UGT1A1*28 and cardiovascular disease (CVD) events has be

36 There was no association between UGT1A1*28 genotype and toxicity or pharmacokinetic param

37 ncrease in AUC of drugs primarily cleared by UGT1A1 or 2B17.

38 f the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 -48C>T, SLCO1B1*1b, ANC baseline

39 dated bilirubin at 1/10 the level of that by UGT1A1 with a Km (bilirubin) of 25 microM compared to th

40 droquinone and beta-naphthoflavone, cellular UGT1A1 glucuronidation activities were increased.

41 mine the molecular interactions that control UGT1A1 expression, the gene was characterized and induct

42 ple genes, including CYP1A1, CYP1A2, CYP1B1, UGT1A1, UGT1A6, IL6, and SAA1.

43 n the regulation of CYP4F12, CYP3A4, CYP2B6, UGT1A1 and P-glycoprotein.

44 he results suggest that Nrf2-Keap1-dependent UGT1A1 induction by prooxidants might represent a key ad

45 TATAA box of the gene, an allele designated UGT1A1*28, decreases gene transcription.

46 rt) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated wit

47 The liver enzymes UGT1A1 and UGT2B7 formed BPD-7S-Gluc as the major diaste

48 kinetic profiles of a panel of UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B

49 Hepatocellular and biliary tissue expressed UGT1A1 and UGT1A4 but hepatocellular tissue uniquely exp

50 rtium, we suggest twelve new loci (PKN, FN1, UGT1A1, PPARG, DMDGH, PPARD, CDK6, VPS13B, GAD2, GAB2, A

51 6 atazanavir/r recipients were evaluable for UGT1A1.

52 Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or

53 Individuals homozygous for UGT1A1*28 (genotype 7/7) have increased serum bilirubin

54 cal and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic fin

55 bilirubin) of 25 microM compared to that for UGT1A1 of 5.0 microM.

56 To date, four UGT1A1 variant alleles characterized by a variation in t

57 B (n = 124), as well as the known functional UGT1A1*28 and UGT2B17 CNV (copy number variation) polymo

58 ery of clinically predictive genotypes (e.g. UGT1A1*28, TYMS TSER), haplotypes (e.g. VKORC1 Haplotype

59 ations in one of the five exons of the gene (UGT1A1) encoding the uridinediphosphoglucuronate glucuro

60 patients based on their germline genotypes [UGT1A1: 124 probe sets, false discovery rate (FDR)=13%,

61 y used in cancer therapy, such as genotyping UGT1A1 to reduce the incidence of severe toxicity of iri

62 uridine diphosphate-glucuronosyltransferase (UGT1A1).

63 The UDP-glucuronosyltransferase, UGT1A1, is the critical enzyme responsible for detoxific

64 in elimination, UDP-glucuronosyltransferase, UGT1A1.

65 y progression, as in Gilbert's Syndrome (GS; UGT1A1*28 polymorphism), aggravated health effects have

66 olymorphisms in CYP3A4, CYP3A5, MDR1, GSTP1, UGT1A1, and VDR.

67 ined by K(m) analysis was UGT1A10 > UGT1A9 > UGT1A1 > UGT1A7 for (-)-BPD and UGT1A10 > UGT1A9 > UGT2B

68 en considered as a means of inducing hepatic UGT1A1 expression.

69 UGT1 mice show delayed expression of hepatic UGT1A1 and are severely hyperbilirubinemic.

70 greatly reduced due to induction of hepatic UGT1A1.

71 eonatal mice was not associated with hepatic UGT1A1 expression.

72 As a series of hereditary UGT1A1 mutations have been identified that are associate

73 Homozygote UGT1A1*28 allele carriers with higher serum bilirubin co

74 Homozygous UGT1A1*28 GS individuals were simultaneously homozygous

75 The homozygous UGT1A1*28 allele observed in 9% of patients was associat

76 Human UGT1A1 was markedly increased in small and large intesti

77 al that the Ah receptor is involved in human UGT1A1 induction.

78 ons indicate that some mutant forms of human UGT1A1 (hUGT1A1) may be dominant-negative, suggesting th

79 iven the lack of in vivo regulation of human UGT1A1 by chrysin in a transgenic animal model.

80 n of oxidants toward the regulation of human UGT1A1 in vivo, transgenic mice bearing the human UGT1 l

81 ecipient rats against the F-protein or human UGT1A1.

82 cted against the amino terminal of the human UGT1A1 isoform showed that 5 hepatocyte donors exhibited

83 -exposed donors exhibited marked declines in UGT1A1 mRNA levels during culturing.

84 te donors exhibited a >50-fold difference in UGT1A1 level.

85 review the role of genetic polymorphisms in UGT1A1 and TPMT, as well as mutations in DPD, in influen

86 computer program, this hydrophobic region in UGT1A1 is located between residues 159-177 and defines a

87 disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated.

88 in the marked interindividual variability in UGT1A1 expression.

89 The top variants in UGT1A1 and SLCO1B1 explain approximately 18.0 and approx

90 DP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin.

91 locus, encoding all 9-UGT1A genes including UGT1A1, was expressed in Ugt1(-/-) mice.

92 inase signaling pathways to maximally induce UGT1A1.

93 ess the human UGT1 locus is unable to induce UGT1A1 expression in either the small intestine or liver

94 In the hUGT1 mice, glucose induced UGT1A1 in the small intestine, while it did not affect t

95 s an important dietary substance and induces UGT1A1 protein expression in cell culture.

96 Rifampicin (RIF) induces UGT1A1, an enzyme involved in raltegravir (RAL) eliminat

97 Liver and intestinal UGT1A1 were induced, along with murine CYP2B10, a consen

98 d to repression of both liver and intestinal UGT1A1.

99 emia in hUGT1 neonates because of intestinal UGT1A1 gene derepression.

100 Breast milk reduces expression of intestinal UGT1A1, which leads to hyperbilirubinemia and BIND; supp

101 mice because of ROS induction of intestinal UGT1A1.

102 pSB-hUGT1A1 (4-8 microg/day, 1-4 doses) into UGT1A1-deficient hyperbilirubinemic Gunn rats (model of

103 yped for those polymorphisms that are known (UGT1A1*28) or likely (HMOX-1 microsatellites) to impact

104 nst several UGTs (i.e., UGT1A7 by lapatinib; UGT1A1 by imatinib; UGT1A4, 1A7 and 1A9 by axitinib; and

105 microsomal bilirubin UGT activity and liver UGT1A1 mRNA level (r(2) =.82 and.72, respectively).

106 mice to N-acetylcysteine, induction of liver UGT1A1 and CYP2B10 by PEITC was prevented.

107 al 14-day post-conception Tg-UGT1mice, liver UGT1A1, UGT1A4, and UGT1A6 were induced, with the levels

108 In liver, UGT1A1, UGT1A3, UGT1A4, and UGT1A9 are expressed, and ar

109 rinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome,

110 Of the 4 patients with the lowest UGT1A1 levels, 3 were homozygotes for the UGT1A1 promote

111 Tg(UGT1(A1*28))Ugt1(-/-) mice] or the normal UGT1A1*1 allele [Tg(UGT1(A1*1))Ugt1(-/-) mice].

112 A1 promoter repeat polymorphism [A(TA)nTAA] (UGT1A1*28) and GSTM1 deletion were significant predictor

113 s, we emphasize here the impaired ability of UGT1A1 to eliminate bilirubin that contributes to hyperb

114 in Ah receptor recognition and activation of UGT1A1 by chrysin exist when compared with classical mec

115 ed with mRNA expression and/or activities of UGT1A1, UGT1A3 and UGT2B17.

116 ar result was observed following analysis of UGT1A1 expression in liver.

117 analyses suggested a stronger association of UGT1A1 genotype with estrogen receptor (ER)-negative bre

118 idization, we determined the distribution of UGT1A1 and UGT1A7 through UGT1A10 mRNAs and found them f

119 However, polymorphic expression of UGT1A1 (29%), UGT1A3 (21%), and UGT1A6 (36%) was detecte

120 he events that control delayed expression of UGT1A1 during development remain a mystery.

121 ence has verified that delayed expression of UGT1A1 during the early stages of neonatal development i

122 2 and provided evidence of the expression of UGT1A1 in breast cancer tissue, where a positive signal

123 ion-PCR analysis confirmed the expression of UGT1A1 in human liver in the hepatocarcinoma cell line H

124 e, while it did not affect the expression of UGT1A1 in the liver.

125 e would lead to the sufficient expression of UGT1A1 in the small intestine to reduce serum bilirubin

126 lear factor-kappaB and loss of expression of UGT1A1, leading to hyperbilirubinemia.

127 se chain reaction revealed the expression of UGT1A1, UGT1A3, UGT1A4, UGT1A6, and UGT1A9 in the colon,

128 UGT) 1A1, it is now known that immaturity of UGT1A1, in combination with the overproduction of biliru

129 estigated the expression and inducibility of UGT1A1 in human donor livers and their corresponding pri

130 Induction of UGT1A1 by PCN and TCDD is believed to be highly dependen

131 e actively promote PCN and TCDD induction of UGT1A1 in Tg-UGT1 primary hepatocytes.

132 bilirubin, which resulted from induction of UGT1A1 in the gastrointestinal tract.

133 ent (XRE) in support of chrysin induction of UGT1A1 in the human hepatoma cell line HepG2.

134 -4050) were responsible for the induction of UGT1A1 in the intestinal cells.

135 The induction of UGT1A1 proceeded following the overexpression of Nrf2 an

136 nti-oxidative response leads to induction of UGT1A1 through the Nrf2-Keap1 pathway.

137 l interfering RNA revealed that induction of UGT1A1 was not seen in Nrf2 knock-out cells.

138 In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of

139 confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and associ

140 Comparative expression levels of UGT1A1 in intestinal tumors and normal surrounding tissu

141 t when compared with classical mechanisms of UGT1A1 induction by TCDD.

142 rious mutations in this microregion (MRA) of UGT1A1 in CN-I patients are evidence of a critical and d

143 he -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requ

144 Methods for absolute quantification of UGT1A1 and UGT1A6 were previously established utilizing

145 to a TA insertion at the promoter region of UGT1A1.

146 servation of differential down-regulation of UGT1A1, UGT1A3, UGT1A6, and UGT1A10 and up-regulation of

147 nts that control developmental repression of UGT1A1 and hyperbilirubinemia.

148 tions are warranted to elucidate the role of UGT1A1 in breast cancer risk.

149 hyperbilirubinemia because of suppression of UGT1A1 in the gastrointestinal tract.

150 pping experiments including transfections of UGT1A1 reporter gene constructs into HepG2 cells coupled

151 ew discusses the role of genetic variants of UGT1A1, TS and EGFR to exemplify the potential impact of

152 The dependence of the XRE on UGT1A1-luciferase activity was demonstrated by a loss of

153 the UGT1A1 (TA) 7/7 genotype from the other UGT1A1 genotypes included HDAC1, RELA and SLC2A1; those

154 Three hundred GS patients (UGT1A1*28 homozygous) and 249 healthy blood donors (HBD)

155 With the recombinant UGT1A1 enzyme and its mutants, P167G, F170del, F170L, F1

156 Thus, PXR serves to repress UGT1A1 gene expression during development.

157 methylcholanthrene (2.5 micromol/L) revealed UGT1A1-inducing effects of phenobarbital, oltipraz, and,

158 GT1 mice that expressed either the Gilbert's UGT1A1*28 allele [Tg(UGT1(A1*28))Ugt1(-/-) mice] or the

159 finding that is independent of the Gilbert's UGT1A1*28 promoter polymorphism.

160 In this study, UGT1A1 expression levels were determined in the liver an

161 ction of FDA approved pharmacogenetic tests (UGT1A1*28) and the initiation of a genotype-guided clini

162 her glucuronidation of 17beta-estradiol than UGT1A1.

163 unoprecipitation results also confirmed that UGT1A1 was capable of forming heterodimer complexes with

164 These results demonstrate that UGT1A1 is the isoform responsible for SN-38 glucuronidat

165 This technique demonstrated that UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9,

166 re also explored, and it was determined that UGT1A1 was capable of binding with UGT1A3, UGT1A4, UGT1A

167 Our findings suggest that UGT1A1 may be a major gene controlling serum bilirubin l

168 The UGT1A1 6/6 genotype predicted lower catechol AUC.

169 The UGT1A1 6/6, VDR intron 8 GG, and VDR Fok 1 CC genotypes

170 The UGT1A1 enzyme is a major UGT involved in estradiol glucu

171 The UGT1A1 gene has been shown to be inducible by nuclear re

172 The UGT1A1*28 genotype can be used to individualize dosing o

173 The UGT1A1*28 variant has been associated with hyperbilirubi

174 xpress the entire UGT1 locus (hUGT1) and the UGT1A1 gene, develop neonatal hyperbilirubinemia, with 8

175 e found significant associations between the UGT1A1*28 allele and decreased risk of CVD.

176 show that in human hepatoma HepG2 cells the UGT1A1 gene is also inducible with aryl hydrocarbon rece

177 Genes whose expression distinguished the UGT1A1 (TA) 7/7 genotype from the other UGT1A1 genotypes

178 st UGT1A1 levels, 3 were homozygotes for the UGT1A1 promoter variant sequence associated with Gilbert

179 In GS the UGT1A1*28 variant reduces bilirubin conjugation by 70% a

180 consequence of a deleterious mutation in the UGT1A1 (HUG-Br1) isozyme of a Crigler-Najjar (CN) Type I

181 r type I disease results from lesions in the UGT1A1 gene and is often fatal.

182 depending on the number of TA repeats in the UGT1A1 promoter region.

183 racterized by an allelic polymorphism in the UGT1A1 promoter, hyperbilirubinemia was monitored in hum

184 has been known to increase expression of the UGT1A1 gene in liver.

185 be prevented by enhancing regulation of the UGT1A1 gene in neonatal mice.

186 Steroid induction of the UGT1A1 gene indicates that xenobiotic sensors, such as t

187 ification of SN-38, whereas induction of the UGT1A1 gene may serve to limit toxicity and improve the

188 Transcriptional silencing of the UGT1A1 gene was relieved in neonatal hUGT1 hepatocytes t

189 f a developmental delay in expression of the UGT1A1 gene, were treated with PEITC, TSB levels were re

190 istal enhancer sequence (-3483/-3194) of the UGT1A1 gene.

191 ions in the noncoding intronic region of the UGT1A1 gene.

192 oth a positive and negative regulator of the UGT1A1 gene.

193 bital-response enhancer module region of the UGT1A1 gene.

194 that Keap1 suppresses Nrf2 activation of the UGT1A1 gene.

195 Here, we show permanent correction of the UGT1A1 genetic defect in Gunn rat liver with site-specif

196 Our results indicate that correction of the UGT1A1 genetic lesion in the Gunn rat restores enzyme ex

197 c influence on serum bilirubin levels of the UGT1A1 locus (P < 5 x 10(-324)) and a 12p12.2 locus.

198 t only the proximal region (-1300/-7) of the UGT1A1 promoter, but also distal region (-6500/-4050) we

199 the examination of the responsiveness of the UGT1A1 to PB in the human population, particularly indiv

200 Of the 16 loci, only the UGT1A1 promoter repeat polymorphism [A(TA)nTAA] (UGT1A1*

201 entify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability

202 f nuclear proteins specifically bound to the UGT1A1-XRE, and competition experiments with Ah receptor

203 ved only in HK293 cells transfected with the UGT1A1 isozyme.

204 he promoter polymorphism associated with the UGT1A1*28 allele contributes to hyperbilirubinemia in mi

205 ingle guanosine (G) base deletion within the UGT1A1 gene.

206 Therefore, UGT1A1 genotyping is not a useful prognostic indicator o

207 Nucleotide sequence analysis of this UGT1A1 enhancer region revealed a xenobiotic response el

208 atment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-

209 djusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly

210 ical tests for toxicity avoidance (eg, TPMT, UGT1A1) and efficacy prediction (eg, epidermal growth fa

211 blood donors (HBD) were genotyped for UGT1A (UGT1A1*28, UGT1A3-66 T>C, UGT1A6*3a, UGT1A7*3) and trans

212 cription levels of five major hepatic UGT1A (UGT1A1, UGT1A3, UGT1A4, UGT1A6 and UGT1A9) and five UGT2

213 corresponding immunoblot showed that UGT1A6, UGT1A1, and CYP3A4 were immunoprecipitated.

214 Western blots showed that UGT2B7, UGT1A6, UGT1A1, and CYP3A4 were successfully immunoprecipitated

215 with specific antibodies to UGT2B7, UGT1A6, UGT1A1, and CYP3A4, and the immunoprecipitates were run

216 We suggest that the unstable UGT1A1 polymorphism may serve to "fine-tune" the plasma

217 y that differed between the two clusters was UGT1A1 (P=0.002; Fisher's exact test).

218 77.1 mul.min(-1).mg of protein(-1)), whereas UGT1A1 was most efficient at forming AalphaC-HON(2)-Gl (

219 zed estrogens and their derivatives, whereas UGT1A1, -1A3, -1A7, and -1A8 differentially exhibited re

220 eart Study population to investigate whether UGT1A1*28 is associated with the risk of CVD events.

221 ave been identified that are associated with UGT1A1 deficiency, new evidence has verified that delaye

222 erall glucuronidation of BPD in humans, with UGT1A1, UGT1A7, UGT1A9, UGT1A10 and potentially UGT1A8 p