Influence of glutathione S-transferase B (ligandin) on the intermembrane transfer of bilirubin. Implications for the intracellular transport of nonsubstrate ligands in hepatocytes.

Zucker, Stephen D.; Goessling, Wolfram; Ransil, Bernard J.; Gollan, John L.

doi:10.1172/jci118238

Cited by 22 publications

(14 citation statements)

References 63 publications

(62 reference statements)

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“…They are good examples of combined effects of mutations of UGT1A1 and other genes. Recently, two other proteins related to neonatal jaundice have been investigated with regard to overflow of nonconjugated bilirubin from the liver; transporter proteins of bilirubin in hepatic cells encoded by the organic anion transporter 2 gene (OATP2 or SLC21A6) (31,32) and the glutathione-Stransferase gene (GST) (33,34). However, combined effects of c.-3279TϾG in UGT1A1 and hemolytic disorder-causing genes and combined effects of c.-3279TϾG and OATP2 (or GST) mutations remain to be clarified.…”

Section: Discussionmentioning

confidence: 99%

A Polymorphic Mutation, c.-3279T>G, in the UGT1A1 Promoter Is a Risk Factor for Neonatal Jaundice in the Malay Population

et al. 2010

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ABSTRACT:The uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene encodes the enzyme responsible for bilirubin glucuronidation. To evaluate the contribution of UGT1A1 promoter mutations to neonatal jaundice, we determined the genotypes of c.-3279TϾG, c.-3156GϾA, and A(TA)7TAA in Malay infants with neonatal jaundice (patients) and in infants without neonatal jaundice (controls). In our population study, only c.-3279TϾG was associated with neonatal jaundice. The genotype distributions between both groups were significantly different (p ϭ 0.003): the frequency of homozygosity for c.-3279G was much higher in patients than those in controls. Allele frequency of c.-3279G was significantly higher in patients than those in controls (p ϭ 0.006). We then investigated changes in transcriptional activity because of c.-3279TϾG. Luciferase reporter assay in HepG2 cells demonstrated that transcriptional activity of the c.-3279G allele was significantly lower than that of the c.-3279T allele in both the absence and presence of bilirubin. Luciferase reporter assay in COS-7 cells elucidated that c.-3279TϾG modified the synergistic effects of the nuclear factors associated with transcriptional machinery. In conclusion, the c.-3279TϾG mutation in the UGT1A1 promoter is a genetic risk factor for neonatal jaundice. T he uridine diphospho (UDP)-glucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene encodes bilirubin UDPglucuronosyltransferase (UGT1A1), which is the enzyme responsible for bilirubin glucuronidation. A decrease in UGT1A1 activity leads to unconjugated hyperbilirubinemia. Inherited UGT1A1 deficiencies because of UGT1A1 mutations are classified into three forms based on clinical severity: Crigler-Najjar syndrome type 1 (CN-1, a severe form), Crigler-Najjar syndrome type 2 (CN-2, an intermediate form), and Gilbert's syndrome (GS, a mild form) (1,2). Such inherited UGT1A1 deficiencies may cause neonatal jaundice.A mutant TATA box with an additional TA insertion, A(TA)7TAA, was first found in patients with CN-1, CN-2, and GS (3-5). GS with homozygosity for A(TA)7TAA accelerates or prolongs neonatal jaundice (6). This mutation is frequently observed in whites and Africans (7). Another GScausing gene mutation, c.211GϾA, is frequent in the East Asian population (8). The c.211GϾA mutation causes an amino acid change, glycine to arginine at codon 71.Recently, polymorphic mutations, c.-3279TϾG and c.-3156GϾA, were identified in the UGT1A1 promoter region (9,10). The c.-3279TϾG mutation is located in the phenobarbital responsive enhancer module (gtPBREM), which is activated by a nuclear receptor, constitutive androstane receptor (CAR) (11). Sugatani et al. (9) showed using luciferase reporter assay that mutant gtPBREM with c.-3279TϾG decreases the transcriptional activity of the UGT1A1 promoter by 60%. The c.-3156GϾA mutation is located between the gtPBREM and TATA box. A haplotype analysis showed that there is a high extent of linkage disequilibrium between c.-3156GϾA and A(TA)7TAA (10,12). However, it is unknown ...

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Section: Discussionmentioning

confidence: 99%

A Polymorphic Mutation, c.-3279T>G, in the UGT1A1 Promoter Is a Risk Factor for Neonatal Jaundice in the Malay Population

et al. 2010

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“…Proteins of class A GSTs bind to bilirubin with a higher affinity than those of the M and T classes [10,24,28,31,38]. Contrary to this generally held concept regarding the role of GSTs in the intracellular transport of nonsubstrate ligands, Boyer and Whalen suggested that all of the GSTs appear to bind to nonsubstrate ligands such as bilirubin [2,37].…”

Section: Discussionmentioning

confidence: 99%

Are glutathione S-transferase gene polymorphisms linked to neonatal jaundice?

et al. 2007

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Glutathione S-transferases (GSTs) are a major group of phase II detoxification enzymes involved in the metabolism of both endogenous and xenobiotic compounds. In addition to their catalytic function in detoxification, GSTs participate in binding to nonsubstrate ligands such as bilirubin. Ligandin, which is one of the principal hepatic-binding proteins, is also a member of the GST family. The aim of the present study was to investigate the possible relationship between neonatal jaundice and the GST gene polymorphisms. The study cohort consisted of a patient group of 116 newborns (plasma bilirubin levels > or = 15 mg/dl) and a control group of 54 newborns (plasma bilirubin levels <13 mg/dl). In the patient group, the null genotype frequencies in GSTM1 and GSTT1 were 52.6 and 19%, respectively; in the control group, these were 63 and 27.8%, respectively. The frequencies of GSTM1 and GSTT1 were similar in the patient and control groups (p > 0.05). Total bilirubin levels were found to be significantly higher in patients with the GSTM1 null genotype than in patients with the GSTM1 wild genotype (p = 0.042). There was no statistically significant difference in total bilirubin levels between patients with the null GSTT1 genotype and those with the wild GSTT1 genotype. It is conceivable that there is a relation between GSTM1 gene polymorphism and total bilirubin levels in neonatal jaundice. We suggest that GSTM1 gene polymorphisms may affect ligandin functions in hepatocytes, which are important in bilirubin transportation. Consequently, patients with the GSTM1 null genotype may have higher total levels of bilirubin.

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“…In addition to detoxification, certain GSTs such as the alpha class GST isoforms in humans (hGSTA1-1) (Zucker et al, 1995) and rats (rGSTA1-1, rGSTA3-3) (Sheehan and Mantle, 1984), as well as human pi-class GST (hGSTP1-1) (Caccuri et al, 1990;Kaplowitz, 1980;Oakley et al, 1999) exhibit ligandin properties by binding and sequestering endogenous and exogenous compounds (Hayes and Pulford, 1995;Singer and Litwack, 1971;Tipping and Ketterer, 1981;Tipping et al, 1976). Ligandin substrates can include toxicants such as reactive metabolites formed from carcinogens (Arias et al, 1980;Kirsch et al, 1975) as well as endogenous compounds such as heme and bilirubin (da Silva Vaz et al, 2004;Di Ilio et al, 1995;Litwack et al, 1971).…”

Section: Discussionmentioning

confidence: 99%

Characterization of hepatic glutathione S-transferases in coho salmon (Oncorhynchus kisutch)

et al. 2007

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The glutathione S-transferases (GSTs) are a family of phase II detoxification enzymes which protect against chemical injury. In contrast to mammals, GST expression in fish has not been extensively characterized, especially in the context of detoxifying waterborne pollutants. In the Northwestern United States, coho salmon (Oncorhynchus kisutch) are an important species of Pacific salmon with complex life histories that can include exposure to a variety of compounds including GST substrates. In the present study we characterized the expression of coho hepatic GST to better understand the ability of coho to detoxify chemicals of environmental relevance. Western blotting of coho hepatic GST revealed the presence of multiple GST-like proteins of approximately 24-26 kDa. Reverse phase HPLC subunit analysis of GSH affinity-purified hepatic GST demonstrated six major and at least two minor potential GST isoforms which were characterized by liquid chromatography electrospray ionization tandem mass spectrometry (LC/ ESI MS-MS) and Fourier transform-ion cyclotron resonance (FT-ICR) MS analyses. The major hepatic coho GST isoforms consisted of a pi and a rho-class GST, whereas GSTs representing the alpha and mu classes constituted minor isoforms. Catalytic studies demonstrated that coho cytosolic GSTs were active towards the prototypical GST substrate 1-chloro-2,4-dinitrobenzene, as well as towards ethacrynic acid and nitrobutyl chloride. However, there was no observable cytosolic GST activity towards the pesticides methyl parathion or atrazine, or products of oxidative stress, such as cumene hydroperoxide and 4-hydroxynonenal. Interestingly, coho hepatic cytosolic fractions had a limited ability to bind bilirubin, reflecting a potential role in the sequestering of metabolic by-products. In summary, coho salmon exhibit a complex hepatic GST isoform expression profile consisting of several GST classes, but may have a limited a capacity to conjugate substrates of toxicological significance such as pesticides and endogenous compounds associated with cellular oxidative stress.

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Influence of glutathione S-transferase B (ligandin) on the intermembrane transfer of bilirubin. Implications for the intracellular transport of nonsubstrate ligands in hepatocytes.

Cited by 22 publications

References 63 publications

A Polymorphic Mutation, c.-3279T>G, in the UGT1A1 Promoter Is a Risk Factor for Neonatal Jaundice in the Malay Population

A Polymorphic Mutation, c.-3279T>G, in the UGT1A1 Promoter Is a Risk Factor for Neonatal Jaundice in the Malay Population

Are glutathione S-transferase gene polymorphisms linked to neonatal jaundice?

Characterization of hepatic glutathione S-transferases in coho salmon (Oncorhynchus kisutch)

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