RT Journal Article
SR Electronic
T1 Age-Related Changes in Expression and Activity of Human Hepatic Mitochondrial Glutathione Transferase Zeta1
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.081810
DO 10.1124/dmd.118.081810
A1 Guo Zhong
A1 Margaret O. James
A1 Marci G Smeltz
A1 Stephan C Jahn
A1 Taimour Y Langaee
A1 Pippa Simpson
A1 Peter W Stacpoole
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/05/31/dmd.118.081810.abstract
AB Glutathione transferase zeta1 (GSTZ1) catalyzes glutathione (GSH)-dependent dechlorination of dichloroacetate (DCA), an investigational drug with therapeutic potential in metabolic disorders and cancer. GSTZ1 is expressed in both hepatic cytosol and mitochondria. The ontogeny of human cytosolic GSTZ1 has been investigated. Here, we examined the ontogeny of human mitochondrial GSTZ1 and characterized the properties of mitochondrial GSTZ1. GSTZ1 expression and activity with DCA were determined in 103 human hepatic mitochondrial samples prepared from livers of donors aged 1 day to 84 years. Each sample was genotyped for the major GSTZ1 variants. Expression of mitochondrial GSTZ1 protein increased in an age-dependent manner to a plateau after age 21 years. Activity with DCA correlated with expression, after taking into account the higher activity of samples that were homo- or heterozygous for the GSTZ1A variant. In samples from livers with the GSTZ1C variant, apparent enzyme kinetic constants for DCA and GSH were similar for mitochondria and cytosol after correcting for the loss of GSH observed in mitochondrial incubations. In the presence of 38 mM chloride, mitochondrial GSTZ1 exhibited shorter half-lives of inactivation compared with the cytosolic enzyme (p=0.017). GSTZ1 protein isolated from mitochondria was shown by mass spectrometry to be identical to cytosolic GSTZ1 protein in the covered primary protein sequence. In summary, we report age-related development in the expression and activity of human hepatic mitochondrial GSTZ1 does not have the same pattern as that reported for cytosolic GSTZ1. Some properties of cytosolic and mitochondrial GSTZ1 differed, but these were not related to differences in amino acid sequence or post-translationally modified residues.