Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

1.   Wenjun Li,
2.   Yuan Gu,
3.   Margaret O. James,
4.   Ronald N. Hines,
5.   Pippa Simpson,
6.   Taimour Langaee,
7.   Peter W. Stacpoole

+ Author Affiliations

1.   Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin (R.N.H., P.S.); Departments of Medicinal Chemistry (W.L., Y.G., M.O.J.); Pharmacotherapy and Translational Research (T.L.) and Center for Pharmacogenomics (T.L.); College of Pharmacy; Departments of Medicine and Biochemistry and Molecular Biology (P.W.S.); College of Medicine, University of Florida, Gainesville,

1. Address correspondence to:
   Address: P.O. Box 100485, Gainesville, FL 32610-0485, Department of Medicinal Chemistry, Health Science Center P6-20, University of Florida. E-mail:mojames@ufl.edu
2. This study has previously been presented in part as follows: Gu Y, Li W, Langaee T, James MO, Hines RN, and Stacpoole PW Expression and activity of glutathione transferase Z1 during oncogenesis in human liver cytosol. 2010 September 4–8, Istanbul, Turkey: Ninth International Meeting of the International Society for the Study of Xenobiotics. Washington, DC-based International Society for the Study of Xenobiotics
3. 1. W.L. and Y.G. both made equal contributions to this work.

Link: https://dmd.aspetjournals.org/content/40/2/232.abstract

Abstract

Maleylacetoacetate isomerase, also known as glutathione transferase 1 (GSTZ1), catalyzes the penultimate step of tyrosine catabolism and metabolizes a number of -halocarboxylic acids, including dichloroacetic acid (DCA), a recently discovered investigational treatment for solid tumors and lactic acidosis. DCA pharmacotoxicology has shown age-related changes, but there is no data on GSTZ1 ontogeny in humans. Using human livers from donors between 10 weeks gestation and 74 years old, we looked at the cytosolic GSTZ1 developmental expression pattern and the effect of haplotype on GSTZ1 activity in this study. In fetal livers, there was very little GSTZ1 expression (2 pmol of GSTZ1/mg cytosol). After birth, the expression increased in an age-dependent manner until 7 years old. After that, GSTZ1 was maintained at steady but variable levels until the age of 74 (median, 20.0 pmol/mg cytosol; range, 4.8-47.3 pmol/mg cytosol). With DCA, GSTZ1 activity was highly correlated with haplotype and expression level. At a specific level of expression, samples homozygous or heterozygous for GSTZ1A showed about three times more DCA dechlorinating activity than samples bearing other alleles. The correlations (r2) between activity and expression for GSTZ1A carriers (n = 11) and noncarriers (n = 61) were 0.90 and 0.68, respectively. In addition to the cytosol, mitochondria also express GSTZ1. Similar changes were seen in the mitochondrial fraction due to the GSTZ1A genotype, which increased DCA activity. In conclusion, we reveal that GSTZ1 protein expression during human liver development has a neonatal onset and rises with age. GSTZ1 activity with DCA was altered by haplotype but not protein expression.

Footnotes

National Institutes of Health National Institute of Environmental Health Sciences [Grants ES007355, ES014617] (to P.W.S.) and National Institutes of Health National Institute of General Medical Sciences [Grant GM081344] both provided funding in support of this research (to R.N.H.).

Information about the article, its release date, and its citations can be found at https://dmd.aspetjournals.org.

doi:https://dx.doi.org/10.1124/dmd.111.041533.

↵ The article’s online version may be found at https://dmd.aspetjournals.org) contains supplemental material.

ABBREVIATIONS:

GSTZ1

1 glutathione transferase

DCA

dichloroacetate

MAAI

isomerase for maleylacetoacetate

SNP

single nucleotide variation

LOQ

a measure of quantity.

Awarded on July 5, 2011.

October 25, 2011, accepted

The American Society for Pharmacology and Experimental Therapeutics is the copyright holder as of 2012.