Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Paper
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

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 ≥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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bhagavan NV (2002) Metabolism of iron and heme. In: Bhagavan NV (ed) Medical biochemistry, 4th edn. Harcourt Academic Press, Orlando, pp 689–696

    Google Scholar 

  2. Boyer TD (1986) Covalent labeling of the nonsubstrate ligand-binding site of glutathione S-transferases with bilirubin-Woodward’s reagent K. J Biol Chem 261:5363–5367

    PubMed  CAS  Google Scholar 

  3. Chen H, Sandler D, Taylor J, Shore D, Liu E, Bloomield C, Bell D (1996) Increased risk of myelodysplastic syndromes in individuals with glutathione transferase theta 1 (GSTT1) gene defect. Lancet 347:295–297

    Article  PubMed  CAS  Google Scholar 

  4. Chowdhury RJ, Chowdhury NR, Wolkoff AW, Arias IM (2001) Hereditary jaundice and disorders of bilirubin metabolism. In: Scriver CR, Beaudet AL, Sly WS, Vale D, Childs B, Kinzler WK, Vogelstein B (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 3063–3101

    Google Scholar 

  5. Dennery PA, Seidman DS, Stevenson DK (2001) Neonatal hyperbilirubinemia. N Eng J Med 344:581–590

    Article  CAS  Google Scholar 

  6. d'Errico A, Taioli E, Chen X, Vineis P (1996) Genetic metabolic polymorphisms and the risk of cancer: a review of the literature. Biomarkers 1:149–173

    Article  CAS  Google Scholar 

  7. Ding VDH, Pickett CB (1985) Transcriptional regulation of rat liver glutathione S-transferase genes by phenobarbital and 3-methylcholanthrene. Arc Biochem Biophys 240:553–559

    Article  CAS  Google Scholar 

  8. Eaton DL, Bammler TK (1999) Concise review of the glutathione s-transferases and their significance to toxicology. Toxicol Sci 49:156–164

    Article  PubMed  CAS  Google Scholar 

  9. Eder AF, Manno CS (2004) Alloimmune hemolytic disease of the fetus and newborn. In: Greer JP, Foerster J, Lukens JN, Rodgers GM, Paraskevas F, Glader B (eds) Wintrobe’s clinical hematology, 11th edn. Lippincot, Williams and Willkins, Philadelphia, pp 1184–1200

    Google Scholar 

  10. Gallagher EP, Gardner JL (2002) Comparative expression of two alpha class glutathione S-transferases in human adult and prenatal liver tissues. Biochem Pharmacol 63:2025–2036

    Article  PubMed  CAS  Google Scholar 

  11. Gartner LM, Lee KS, Morecki R (1992) Jaundice and liver disease. In: Fanaroff AA, Martin RJ (eds) Neonatal-prenatal medicine disease of the fetus and infant, 5th edn. Mosby-Year Book, St. Louis, Mo., pp 1075–1118

    Google Scholar 

  12. Hayes JD, Pulford DJ (1995) The glutathione S-transferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30:445–600

    PubMed  CAS  Google Scholar 

  13. Igarashi T, Irokawa N, Ono S, Ohmori S, Ueno K, Kitagawa H (1987) Difference in the effects of phenobarbital and 3-methylcholanthrene treatment on subunit composition of hepatic glutathione S-transferase in male and female rats. Xenobiotica 17:127–137

    Article  PubMed  CAS  Google Scholar 

  14. Jonas MM (2003) The liver and bile duct. In: Rudolph CD, Rudolph MA, Hotetter KM, Liter G, Siegel NJ (eds) Rudolph’s pediatrics, 21st edn. McGraw-Hill, Philadelphia, pp 1133–1150

    Google Scholar 

  15. Kelsey KT, Wrensch M, Zuo ZF, Miike R, Wiencke JK (1997) A population-based case-control study of the CYP2D6 and GSTT1 polymorphisms and malignant brain tumors. Pharmacogenetics 7:463–468

    Article  PubMed  CAS  Google Scholar 

  16. Kihara M, Noda K, Okamoto N (1993) Increased risk of lung cancer in Japanese smokers with class mu glutathione S-transferase gene deficiency. Cancer Lett 71:151–155

    Article  PubMed  CAS  Google Scholar 

  17. Ko Y, Koch B, Harth V, Sachinidis A, Thier R, Vetter H, Bolt HM, Brüning T (2000) Rapid analysis of GSTM1, GSTT1 and GSTP1 polymorphisms using real-time polymerase chain reaction. Pharmacogenetics 10:1–4

    Article  Google Scholar 

  18. Landi S (2000) Mammalian class theta GST and differential susceptibility to carcinogens: a review. Mutat Res 463:247–283

    Article  PubMed  CAS  Google Scholar 

  19. Listowsky I, Abramovitz M, Homma H, Niitsu Y (1988) Intracellular binding and transport of hormones and xenobiotics by glutathione S-transferases. Drug Metab Rev 19:305–318

    Article  PubMed  CAS  Google Scholar 

  20. Madon A, Stevenson DK (2003) Jaundice in the Newborn. In: Rudolph CD, Rudolph MA, Hotetter KM, Liter G, Siegel NJ (eds) Rudolph’s pediatrics, 21st ed. McGraw-Hill, Philadelphia, pp 164–166

    Google Scholar 

  21. Maisels MJ, Baltz RD, Bhutani VK, Newman TB, Rosenfeld W, Stevenson DK, Weinblatt HB, Homer CJ, Herrerias C (2001) Neonatal jaundice and kernicterus. Pediatrics 108:763–765

    Article  Google Scholar 

  22. Maisels MJ (1994) Neonatal jaundice. In: Avery GL, Fletcher MA, MacDonald MG (eds) Neonatology pathophysiology and management of the newborn, 4th edn. JB Lippincott, Philadelphia, pp 630–725

    Google Scholar 

  23. Mera N, Ohmori S, Itahashi K, Kiuchi M, Igarashi T, Rikihisa T, Kitada M (1994) Immunochemical evidence fort he occurrence of Mu class glutathione S-transferase in human fetal livers. J Biochem 116:315–320

    PubMed  CAS  Google Scholar 

  24. Mulder TPJ, Court DA, Peters WHM (1999) Variability of glutathione S-transferase A in human liver and plasma. Clin Chem 45:355–359

    PubMed  CAS  Google Scholar 

  25. Nelson DL, Cox MM (2000) Lehninger principles of biochemistry, 3rd edn. Worth Publ, New York, pp 36–437

    Google Scholar 

  26. Porter ML, Dennis BL (2002) Hyperbilirubinemia in the term newborn. Am Fam Physician 65:599–606

    PubMed  Google Scholar 

  27. Rebbeck TR (1997) Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev 6:733–743

    PubMed  CAS  Google Scholar 

  28. Sayed Y, Hornby JA, Lopez M, Dirr H (2002) Thermodynamics of the ligandin function of human class Alpha glutathione transferase A1-1: energetics of organic anion ligand binding. Biochem J 363:341–346

    Article  PubMed  CAS  Google Scholar 

  29. Seidegard J, Ekström G (1997) The role of human glutathione transferases and epoxide hydrolases in the metabolism of xenobiotics. Environ Health Perspect 105:791–799

    Article  PubMed  CAS  Google Scholar 

  30. Seidegard J, Pero RW, Markowitz MM, Roush G, Miller DG, Beattie EJ (1990) Isoenzyme(s) of glutathione transferase (class mu) as a marker for susceptibility to lung cancer: a follow up study. Carcinogenesis 11:33–36

    Article  PubMed  CAS  Google Scholar 

  31. Sheehan D, Meade G, Foley VM, Dowd CA (2001) Structure, function and evolution of glutathione transferases: implications for classifcation of non-mammalian members of an ancient enzyme superfamily. Biochem J 360:1–16

    Article  PubMed  CAS  Google Scholar 

  32. Sherlock SA, Dooley J (2000) Disease of the liver and biliary system, 11th edn. Blackwell Science, Milan, pp 205–217

    Google Scholar 

  33. Sherratt PJ, Pulford DJ, Harrison DJ, Gren T, Hayes JD (1997) Evidence that human class Theta glutathione S-transferase T1-1 can catalyse the activation of the tissue distribution of GSTT1-1 with that of class Alpha, Mu and Pi GST in human. Biochem J 326:837–846

    PubMed  CAS  Google Scholar 

  34. Stoll BJ, Kliegman RM (2000) The fetus and the neonatal infant. In: Berhman RE, Kliegman RM, Jenson HB (eds) Nelson textbook of pediatrics, 16th edn. WB Saunders, Philadelphia, pp 513–526

    Google Scholar 

  35. Strange RC, Matharoo B, Faulder GC, Jones P, Cotton W, Elder JB, Deakin M (1991) The human glutathione S-transferases: a case-control study of the incidence of the GST1 0 phenotype in patients with adenocarcinoma. Carcinogenesis 12:25–28

    Article  PubMed  CAS  Google Scholar 

  36. Ünal M, Tamer L, Aras Ates N, Akbas Y, Pata YS, Vayısoglu Y, Ercan B, Gorur K, Atik U (2004) Glutathione S-transferase M1, T1 and P1 gene polymorphism in laryngealsquamus cell carcinoma. Am J Otolaryngol 25:318–321

    Article  PubMed  CAS  Google Scholar 

  37. Whalen R, Boyer TD (1988) Human glutathione S-transferases. Semin Liver Dis 18:345–358

    Article  Google Scholar 

  38. Zucker SD, Goessling W, Ransil BJ, Gollan JL (1995) Influence of glutathione S-transferase B (ligandin) on the intermembrane transfer of bilirubin. Implications for the intracellular transport of nonsubstrate ligands in hepatocytes. J Clin Invest 96:1927–1935

    Article  PubMed  CAS  Google Scholar 

  39. Zucker SD, Goessling W, Zeidel ML, Gollan JL (1994) Membrane lipid composition and vesicle size modulate bilirubin intermembrane transfer: evidence for membrane-directed trafficking of bilirubin in the hepatocyte. J Biol Chem 269:19262–19270

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Mersin University Medical Faculty, Mersin, Turkey

    Necati Muslu, Zeynep Nil Dogruer, Gulcin Eskandari & Ugur Atik

  2. Department of Pediatrics, Mersin University Medical Faculty, Mersin, Turkey

    Aytug Atici

  3. Department of Biostatistics, Mersin University Medical Faculty, Mersin, Turkey

    Seval Kul

Authors
  1. Necati Muslu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zeynep Nil Dogruer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gulcin Eskandari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aytug Atici
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seval Kul
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ugur Atik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Necati Muslu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Muslu, N., Dogruer, Z.N., Eskandari, G. et al. Are glutathione S-transferase gene polymorphisms linked to neonatal jaundice?. Eur J Pediatr 167, 57–61 (2008). https://doi.org/10.1007/s00431-007-0425-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-007-0425-z

Keywords

Search

Navigation