Decreased Glutathione S-transferase Level and Neonatal Hyperbilirubinemia Associated with Glucose-6-phosphate Dehydrogenase Deficiency: A Perspective Review

Abstract

Classically, genetically decreased bilirubin conjugation and/or hemolysis account for the mechanisms contributing to neonatal hyperbilirubinemia associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, these mechanisms are not involved in most cases of this hyperbilirubinemia. Additional plausible mechanisms for G6PD deficiency-associated hyperbilirubinemia need to be considered. Glutathione S-transferases (GST) activity depends on a steady quantity of reduced form of glutathione (GSH). If GSH is oxidized, it is reduced back by glutathione reductase, which requires the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH). The main source of NADPH is the pentose phosphate pathway, in which G6PD is the first enzyme. Rat kidney GSH, rat liver GST, and human red blood cell GST levels have been found to positively correlate with G6PD levels in their respective tissues. As G6PD is expressed in hepatocytes, it is expected that GST levels would be significantly decreased in hepatocytes of G6PD-deficient neonates. As hepatic GST binds bilirubin and prevents their reflux into circulation, hypothesis that decreased GST levels in hepatocytes is an additional mechanism contributing to G6PD deficiency-associated hyperbilirubinemia seems plausible. Evidence for and against this hypothesis are discussed in this article hoping to stimulate further research on the role of GST in G6PD deficiency-associated hyperbilirubinemia.

Prolonged indirect hyperbilirubinemia in a moderately preterm boy with Mediterranean glucose-6-phosphate dehydrogenase and glutathioneS-transferase Mu 1 null mutations

“…The GSTM1 is the most expressed GST in the liver, followed by GST-Theta 1 (GSTT1) 5. These GSTs bind cytosolic bilirubin and transfer it to the smooth endoplasmic reticulum for conjugation 5.…”

“…These GSTs bind cytosolic bilirubin and transfer it to the smooth endoplasmic reticulum for conjugation 5. Supposedly, bilirubin will return to the circulation in case of GSTM1 or GSTT1 null allele mutation (zero activity) 5.…”

“…These GSTs bind cytosolic bilirubin and transfer it to the smooth endoplasmic reticulum for conjugation 5. Supposedly, bilirubin will return to the circulation in case of GSTM1 or GSTT1 null allele mutation (zero activity) 5. Results from the studies on the relationship between null allele mutation of GSTM1 (GSTM1*0/*0) or GSTT1 (GSTT1*0/*0) and hyperbilirubinemia are inconsistent 5.…”

“…Supposedly, bilirubin will return to the circulation in case of GSTM1 or GSTT1 null allele mutation (zero activity) 5. Results from the studies on the relationship between null allele mutation of GSTM1 (GSTM1*0/*0) or GSTT1 (GSTT1*0/*0) and hyperbilirubinemia are inconsistent 5. One study found that mean TSB levels were significantly higher in infants with ABO incompatibility and with no GSTM1 activity (GSTM1*0/*0 mutation) compared to infants with ABO incompatibility and with some GSTM1 activity (GSTM1 gene) 11…”

“…Glucose-6-phosphate dehydrogenase (G6PD) deficiency is known to be a risk factor for the PIH 1 3 4. The impetus for this report is the recent suggestion that decreased hepatic glutathione S -transferase (GST) is a plausible mechanism of G6PD deficiency-associated hyperbilirubinemia 5. Thus, a case of PIH in a moderately preterm boy with Mediterranean G6PD and homozygous GST Mu 1 null mutation (GSTM1*0/*0) is presented here.…”