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

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 > 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.

Glutathione S-Transferase Gene Polymorphisms in Neonatal Hyperbilirubinemia

“…GSTT1 null genotype frequencies in cases and control groups were 29.7% and 30%, respectively, with no significant difference ( P = 0.96). Also, this is different from the results reported by Muslu et al 16 who found that GSTM1 and GSTT1 null genotypes in the patient group were 52.6% and 19%, respectively, whereas in the control group, these were 63% and 27.8,% respectively. The frequencies of GSTM1 and GSTT1 in their study were similar in the patient and control groups ( P = 0.215).…”

“…This is in accordance to Muslu et al 16 who observed that total bilirubin levels were significantly higher in jaundiced neonates with GSTM1 null than GSTM1 wild genotypes ( P = 0.042), but there was no statistically significant difference between the total bilirubin levels and the null or wild GSTT1 genotypes. An explanation for this finding in their study was that it may be due to the deletion in GSTM1 gene that causes changes in enzyme activity and messenger RNA levels of the hepatic GST isoform.…”

Genetic polymorphisms in Thai neonates with hyperbilirubinemia

“…The PCR amplification was performed in a DNA thermal cycler for 35 cycles of initial denaturation 5 min, denaturation for 1 min at 94°C, annealing for 1 min at 64°C, primer extension for 1 min at 72°C and a final extension for 7 min at 72°C. The PCR product was digested with the appropriate restriction enzymes and analysed on 3% agarose gel as described previously (3). (The 91 subjects of hyperbilirubinemic group and 80 subjects of control group were studied for GST gene).…”

Inherited disorders of bilirubin clearance

“…SLCO1B1 /OATP1B1 and SLCO1B3 /OATP1B3 mRNA expression is approximately 500-fold lower in neonates and 100-fold lower in infants up to the 12 months of age than in adults (14). GST has multiple classes, with proteins belonging to class alpha (GST-A) having the highest affinity to bilirubin (15). GST-A protein expression is 1.5 to 4-fold lower in newborns and reach adult levels after the first 1–2 years of life (16).…”

“…Recent studies have demonstrated polymorphisms in GST genes that are associated with increased risk of neonatal hyperbilirubinemia (15,20). The most important polymorphism associated with neonatal hyperbilirubinemia is one that encodes for a partial gene deletion in the GST mu (GST-M) gene class.…”