Hepatocyte nuclear factor-1 alpha is associated with UGT1A1, UGT1A9 and UGT2B7 mRNA expression in human liver

Ramı́rez, Jacqueline; Mirkov, Snezana; Zhang, W; P, Chen; Das, Soma; W, Liu; Ratain, Mark J.; Innocenti, Federico

doi:10.1038/sj.tpj.6500454

Cited by 33 publications

(22 citation statements)

References 48 publications

(62 reference statements)

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“…3C), exhibiting a 150-fold variability (Izukawa et al, 2009). Previous studies (Aueviriyavit et al, 2007;Ramírez et al, 2008) reported that HNF1␣ and HNF4␣ mRNA levels were strongly correlated with UGT1A9 mRNA levels in a panel of human livers, which is consistent with the finding that HNF1␣ and HNF4␣ contribute to the regulation of UGT1A9 (Barbier et al, 2005;Gardner-Stephen and Mackenzie, 2007). However, the HNF protein levels rather than mRNA level should be considered.…”

Section: Ugt1a9 Protein Expression In Human Cell Linessupporting

confidence: 83%

Preparation of a Specific Monoclonal Antibody against Human UDP-Glucuronosyltransferase (UGT) 1A9 and Evaluation of UGT1A9 Protein Levels in Human Tissues

Oda¹,

Nakajima²,

Hatakeyama³

et al. 2012

Drug Metabolism and Disposition

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ABSTRACT:Glucuronidation is a major detoxification pathway of drugs and xenobiotics that are catalyzed by the UDP-glucuronosyltransferase (UGT) superfamily. Determination of the protein levels of the individual UGT isoforms in human tissues is required for the successful extrapolation of in vitro metabolic data to in vivo clearance. Most previous studies evaluating UGT isoform expression were limited to the mRNA level because of the high degree of amino acid sequence homology between UGT isoforms that has hampered the availability of isoform-specific antibodies. In this study, we generated a peptide-specific monoclonal antibody against human UGT1A9. We demonstrated that this antibody does not cross-react with the other UGT1A isoforms including UGT1A7, UGT1A8, and UGT1A10 and shows a high degree of amino acid sequence similarity with UGT1A9. Using this antibody, we found that UGT1A9 protein is expressed in the kidney and the liver but not in the jejunum or the ileum, consistent with previous reports of mRNA expression. In a panel of 20 individual human livers, the UGT1A9 protein levels exhibited 9-fold variability. It is noteworthy that the relative UGT1A9 protein levels were not correlated with the UGT1A9 mRNA level (r ‫؍‬ ؊0.13), like other UGT isoforms reported previously, suggesting the importance of evaluating UGT isoform expression at protein levels. In conclusion, we generated a specific monoclonal antibody against UGT1A9 and evaluated the distribution and relative expression levels of the UGT1A9 protein in human tissues. This antibody may serve as a useful tool for further studies of UGT1A9 to evaluate its physiological, pharmacological, and toxicological roles in human tissues.

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Section: Ugt1a9 Protein Expression In Human Cell Linessupporting

confidence: 83%

Preparation of a Specific Monoclonal Antibody against Human UDP-Glucuronosyltransferase (UGT) 1A9 and Evaluation of UGT1A9 Protein Levels in Human Tissues

Oda¹,

Nakajima²,

Hatakeyama³

et al. 2012

Drug Metabolism and Disposition

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“…SNPs of Ϫ2353CϾT and Ϫ997GϾA have no effects on UGT1A1 mRNA levels in this liver sample population. These findings are consistent with previous reports on the effects of these genetic polymorphisms on UGT1A1 transcription (Ramírez et al, 2008), UGT1A1 activity and protein expression in liver microsomes (Peterkin et al, 2007), bilirubin metabolism (Sugatani et al, 2002), and drug metabolism of irinotecan (Innocenti et al, 2002;Kitagawa et al, 2005).…”

Section: Discussionsupporting

confidence: 93%

Genetic Polymorphisms in the TATA Box and Upstream Phenobarbital-Responsive Enhancer Module of the UGT1A1 Promoter Have Combined Effects on UDP-Glucuronosyltransferase 1A1 Transcription Mediated by Constitutive Androstane Receptor, Pregnane X Receptor, or Glucocorticoid Receptor in Human Liver

Li¹,

Buckley²,

Wang³

et al. 2009

Drug Metabolism and Disposition

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ABSTRACT:Transcription of UDP-glucuronosyltransferase (UGT) 1A1 is regulated by the transcription factors, constitutive androstane receptor (CAR), pregnane X receptor (PXR), glucocorticoid receptor (GR), hepatocyte nuclear factor (HNF) 1␣, and HNF4␣. The purpose of this study was to determine whether the genetic polymorphisms in the RNA polymerase II core promoter and the upstream phenobarbital-responsive element module (PBREM) of the UGT1A1 promoter have combined effects on UGT1A1 transcription mediated by the transcription factors. A polymorphism of A(TA) 5-8 TAA in the UGT1A1 TATA box and a single nucleotide polymorphism of ؊3279T>G in PBREM were genotyped in 98 human liver samples. Relative mRNA levels of CAR, PXR, GR, HNF1␣, HNF4␣, and UGT1A1 were quantified by a multiplex branched DNA technique. Correlations of mRNA levels between UGT1A1 and the transcription factors were established in liver samples with different combined genetic polymorphisms. Correlation of mRNA levels between UGT1A1 and CAR, PXR, or GR, but not HNF1␣ or HNF4␣, was abolished in the samples with the combined genotype of TA7/7 plus ؊3279G/G, which was also associated with significantly lower UGT1A1 mRNA levels compared with other combined genotypes. Correlations of mRNA levels between UGT1A1 and CAR or PXR were reduced but not abolished in the samples with the combined genotype of TA6/7 plus ؊3279 G/G, which showed significantly lower UGT1A1 mRNA levels compared with the combined genotype of TA6/7 plus ؊3279T/G and other genotypes containing TA6/6. In conclusion, the combined genotypes containing A(TA) 7 TAA and ؊3279G decrease UGT1A transcription mediated by CAR, PXR, or GR but not by HNF1␣ or HNF4␣.

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“…Transcriptional regulation of the UGT1A gene by transcription factors is more specifically addressed in some following chapters. Variability in these regulatory mechanisms are also accounting for interindividual differences in the glucuronidation pathway (Aueviriyavit, Furihata, Morimoto, Kobayashi, & Chiba, 2007;Mackenzie, Gregory et al, 2005;Ramirez et al, 2008;Toide et al, 2002). In addition, the recent discovery of a new alternatively used exon (referred as exon 5b) in the common region of the locus (exon 2-5) sheds light on innovative mechanisms likely implicated in the control UGT1A-mediated glucuronidation (see next section) Levesque, Girard, Journault, Lepine, & Guillemette, 2007).…”

Section: The Human Ugt1a Family Membersmentioning

confidence: 99%

UGT genomic diversity: beyond gene duplication

Guillemette

Lévesque

Harvey

et al. 2009

Drug Metabolism Reviews

121

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Hepatocyte nuclear factor-1 alpha is associated with UGT1A1, UGT1A9 and UGT2B7 mRNA expression in human liver

Cited by 33 publications

References 48 publications

Preparation of a Specific Monoclonal Antibody against Human UDP-Glucuronosyltransferase (UGT) 1A9 and Evaluation of UGT1A9 Protein Levels in Human Tissues

Preparation of a Specific Monoclonal Antibody against Human UDP-Glucuronosyltransferase (UGT) 1A9 and Evaluation of UGT1A9 Protein Levels in Human Tissues

Genetic Polymorphisms in the TATA Box and Upstream Phenobarbital-Responsive Enhancer Module of the UGT1A1 Promoter Have Combined Effects on UDP-Glucuronosyltransferase 1A1 Transcription Mediated by Constitutive Androstane Receptor, Pregnane X Receptor, or Glucocorticoid Receptor in Human Liver

UGT genomic diversity: beyond gene duplication

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