Ontogeny of hepatic glutathione transferase enzymes in humans

Members of the superfamily of glutathione transferase (GST) enzymes are important in the biotransformation of xenobiotics, including drugs and electrophilic drug metabolites, as well as of endogenous molecules, such as the tyrosine catabolites maleylacetoacetate and maleylacetone.  Developmental changes and genetic variations in drug-metabolizing enzymes are recognized as factors that contribute to age-related and inter-individual differences in both drug efficacy and drug toxicity.  A previous study (1) showed that expression in human liver of members of the GSTA and GSTM classes was low prenatally and increased in the immediate post-natal period to the levels observed in adult liver, whereas expression of GSTP was high in fetal liver early in gestation and dropped during the second trimester and after birth to very low levels in adults.  Examination of the ontogeny of GSTZ1 in human liver showed a distinct developmental pattern.  GSTZ1 protein expression was at or close to detection limits in the pre-natal and immediate post-natal period, then rose during childhood to attain stable, though variable levels between ages 7 and 74 years.  At all ages, the expression of GSTZ1 protein correlated with cytosolic activity towards the GSTZ1 substrate dichloroacetic acid. The correlation of activity with expression was further improved when the influence of the GSTZ1A haplotype, which exhibited a higher ratio of activity:expression, was taken into consideration.  The developmental pattern of GSTZ1 matches what is known of the ontogeny of tyrosine aminotransferase (2) , important in the catabolism of tyrosine to the endogenous substrate for GSTZ1, maleylacetoacetate.  Improving our understanding of the age-related development of drug-metabolizing enzymes is important in appropriate administration of drugs to people, and in understanding susceptibility to environmental chemicals.  Supported in part by the US Public Health Service ES07355 and GM081344.

1.  Strange RC, Howie AF, Hume R, Matharoo B, Bell J, Hiley C, Jones P and Beckett GJ. The developmental expression of alpha- mu- and pi- class glutathione S-transferases in human liver. Biochim. Biophys. Acta. 993:186-190, 989
2. Ohisalo, JJ, Laskowska-Klita, T and Andersson, SM (1982). Development of tyrosine aminotransferase and para-hydroxyphenylpyruvate dioxygenase activities in fetal and neonatal human liver. J Clin Invest 70(1): 198-200