The Association between Prolonged Jaundice and TATA Box Dinucleotide Repeats in Gilbert’s Syndrome

Pasha, Yadollah Zahed; Kacho, Mousa Ahmadpor; Niaki, Haleh Akhavan; Tarighati, Mehdi; Alaee, Ehsan

doi:10.7860/jcdr/2017/19376.10597

Cited by 4 publications

(2 citation statements)

References 12 publications

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“…(2) the hepatic bilirubin-conjugating enzyme uridine-diphosphate glucuronosyl transferase 1A1 (UGT1A1) [13,[15][16][17]19,20,24,28,[30][31][32][33][34][35][36][37][38][39][40][41]; and (3) the hepatic solute carrier organic anion transporter polypeptide 1B1 (OATP1B1)-the bilirubin transporter localized to the sinusoidal membrane of hepatocytes, which is the blood-hepatocyte interface that limits bilirubin hepatic uptake [18][19][20]42]. These genetic variants may interact with each other or with environmental contributors to produce significant NHB [19,20].…”

Section: Introductionmentioning

confidence: 99%

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The Genetics of Glucose-6-Phosphate-Dehydrogenase (G6PD) and Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) Promoter Gene Polymorphism in Relation to Quantitative Biochemical G6PD Activity Measurement and Neonatal Hyperbilirubinemia

Riskin,

Bravdo,

Habib

et al. 2023

Children

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency and polymorphism in uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) were associated with significant neonatal hyperbilirubinemia (NHB) and increased risk for kernicterus. However, quantitative screening tests for G6PD enzyme activity proved unsatisfactory in estimating the risk for significant NHB, especially in heterozygous females that could present phenotype overlap between normal homozygotes, heterozygotes, and deficient homozygotes, resulting in a continuum of intermediate G6PD activity. Objective: To examine the association of genotype and phenotype in newborns with decreased G6PD activity and its relation to NHB. Study design: Quantitative G6PD enzyme activities were measured on umbilical cord blood samples. After accepting parental consent, samples were analyzed for G6PD mutations and UGT1A1 gene polymorphisms (number of TA repeats in the UGT1A1 promoter). The associations to quantitative G6PD activity and bilirubin levels were assessed. Results: 28 females and 27 males were studied. The Mediterranean mutation (NM_001360016.2(G6PD): c.563C>T (p.Ser188Phe)) was responsible for most cases of G6PD deficiency (20 hemizygous males, 3 homozygous and 16 heterozygous females). The association between this mutation, decreased G6PD activity and higher bilirubin levels was confirmed. Heterozygosity to 6/7 TA repeats in the UGT1A1 promoter was associated with increased NHB, especially in female newborns with G6PD deficiency. However, it seems that the interaction between G6PD deficiency, UGT1A1 promoter polymorphism, and NHB is more complex, possibly involving other genetic interactions, not yet described. Despite genotyping females with G6PD deficiency, the overlap between the upper range of borderline and the lower range of normal G6PD activity could not be resolved. Conclusions: The results of this study highlight the possibility for future implementation of molecular genetic screening to identify infants at risk for significant NHB, especially UGT1A1 polymorphism in heterozygous females with borderline G6PD deficiency. However, further studies are needed before such screening could be applicable to daily practice.

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Section: Introductionmentioning

confidence: 99%

“…Alternatively, G6PD mutations can lead to severe NHB by causing low-grade hemolysis coupled with UGT1A1 gene polymorphisms [17,22,[27][28][29][30]35]. UGT1A1 promoter and coding sequence gene variants may cause significant NHB via decreased hepatic bilirubin conjugation [15][16][17][18][30][31][32][33][34][37][38][39][40][41].…”

Section: Introductionmentioning

confidence: 99%

The Genetics of Glucose-6-Phosphate-Dehydrogenase (G6PD) and Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) Promoter Gene Polymorphism in Relation to Quantitative Biochemical G6PD Activity Measurement and Neonatal Hyperbilirubinemia

Riskin,

Bravdo,

Habib

et al. 2023

Children

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The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application Through Physiologically Based Pharmacokinetic Modelling

et al. 2018

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Limited understanding of drug pharmacokinetics in children is one of the major challenges in paediatric drug development. This is most critical in neonates and infants owing to rapid changes in physiological functions, especially in the activity of drug-metabolising enzymes. Paediatric physiologically based pharmacokinetic models that integrate ontogeny functions for cytochrome P450 enzymes have aided our understanding of drug exposure in children, including those under the age of 2 years. Paediatric physiologically based pharmacokinetic models have consequently been recognised by the European Medicines Agency and the US Food and Drug Administration as innovative tools in paediatric drug development and regulatory decision making. However, little is currently known about age-related changes in UDP-glucuronosyltransferase-mediated metabolism, which represents the most important conjugation reaction for xenobiotics. Therefore, the objective of the review was to conduct a thorough literature survey to summarise our current understanding of age-related changes in UDP-glucuronosyltransferases as well as associated clinical and experimental sources of variance. Our findings indicate that there are distinct differences in UDP-glucuronosyltransferase expression and activity between isoforms for different age groups. In addition, there is substantial variability between individuals and laboratories reported for human liver microsomes, which results in part from a lack of standardised experimental conditions. Therefore, we provide a number of best practice recommendations for experimental conditions, which ultimately may help improve the quality of data used for quantitative clinical pharmacology approaches, and thus for safe and effective pharmacotherapy in children.

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JILBER’S SYNDROME: CLINICAL AND PHARMACOLOGICAL ASPECTS. Review

Кhaitovych

Turchak

2020

Med. Sci. of Ukr.

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Relevance. At present, the metabolism of drugs in patients with Gilbert's syndrome will be actively studied, as it may be associated with both the risk of dose-dependent adverse reactions and treatment ineffectiveness. Objective: to summarize the information of various authors on the peculiarities of the use of drugs in patients with Gilbert's syndrome. Methods. Analysis of scientific publications in the international electronic scientometric database PubMed by keywords. Search depth - 10 years (2010-2019). Results. Gilbert’s syndrome is observed in 3-10% of the population and is characterized by an isolated increase of bilirubin in the blood to moderate values without changes in other biochemical parameters of liver function and without damage to its structure. Gilbert's syndrome is inherited autosomal recessively and is mainly due to the presence of an additional dinucleotide thymine-adenine (TA) in the promoter region A(TA)6TAA gene encoding the enzyme UGT1A1. Elongation of the promoter sequence reduces the formation of UGT1A1. Invariant A(TA)7TAA, the level of enzyme production can be reduced to 80% of the norm in hetero- and up to 20% in homozygotes, respectively. Gilbert’s syndrome is manifested by increased levels of indirect bilirubin in the blood, jaundice of the skin and mucous, abdominal pain, as well as dyspepsia, and asthenovegetative syndrome. Intermittent icteric sclera and skin occur against the background of exogenous and endogenous factors such as starvation, dehydration, infectious diseases, emotional and physical stress, hemolysis, menstruation, alcohol consumption, hormonal contraception, etc., usually at a bilirubin concentration exceeding 40-45 μmol/l. Complications of hyperbilirubinemia with Gilbert’s syndrome include the development of gallstone disease, including in children and adolescents. Gilbert’s syndrome is associated with impaired metabolism of some drugs – aglucones. These include anabolic steroids, glucocorticoids, androgens, rifampicin, cimetidine, chloramphenicol, streptomycin, sodium salicylate, ampicillin, caffeine, Ethinyl estradiol, paracetamol, ibuprofen, The clinical feature of Gilbert’s syndrome is the appearance or aggravation of jaundice associated with the use of such drugs. In conditions of UGT1 deficiency, drugs compete with bilirubin for the enzyme, which leads to an increase of indirect bilirubin in the serum. Therefore, to prevent liver damage, it is necessary to assess the risk and benefit of drug treatment of patients with Gilbert’s syndrome in each case. Conclusions. Gilbert’s syndrome is a common pathological condition and therefore it is important to diagnose it as early as possible. Given that the use of aglucones in patients with Gilbert's syndrome may cause the development of drug-induced liver damage, it is necessary to assess the risk and benefit of drug treatment of patients with Gilbert’s syndrome in each case.

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The Association between Prolonged Jaundice and TATA Box Dinucleotide Repeats in Gilbert’s Syndrome

Abstract: The results of this study showed an association between TATA box polymorphism and prolonged jaundice in neonates which revealed that TATA box polymorphism is an important risk to increase and extend icterus.

Cited by 4 publications

References 12 publications

The Genetics of Glucose-6-Phosphate-Dehydrogenase (G6PD) and Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) Promoter Gene Polymorphism in Relation to Quantitative Biochemical G6PD Activity Measurement and Neonatal Hyperbilirubinemia

The Genetics of Glucose-6-Phosphate-Dehydrogenase (G6PD) and Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) Promoter Gene Polymorphism in Relation to Quantitative Biochemical G6PD Activity Measurement and Neonatal Hyperbilirubinemia

The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application Through Physiologically Based Pharmacokinetic Modelling

JILBER’S SYNDROME: CLINICAL AND PHARMACOLOGICAL ASPECTS. Review

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