The influence of human GSTZ1 gene haplotype variations on GSTZ1 expression.
OBJECTIVE
The zeta-1 family isoform of GST biotransforms the investigational drug dichloroacetate (DCA) and certain other halogenated carboxylic acids. Haplotype variability in GSTZ1 influences the kinetics and, possibly, the toxicity of DCA. DCA metabolism correlates with expression of the GSTZ1 protein, so it is important to document variables that affect expression. Following up on a limited previous study, we tested the hypothesis that a coding single nucleotide polymorphism (SNP), the lysine (K) amino acid (E32>K) in GSTZ1 haplotypes linked to a promoter region SNP results in lower hepatic expression of GSTZ1.


METHODS
The influence of K carrier and non-K carrier haplotypes on GSTZ1 expression was determined by analyzing 78 liver samples from individuals aged 7-84 years of various racial and ethnic backgrounds. GSTZ1 expression data were analyzed on the basis of the presence or absence of lysine 32.


RESULTS
GSTZ1 protein expression differed significantly between K carrier and non-K carrier haplotypes (P=0.001) in Whites, but not in African-Americans (P=0.277). We attribute this difference in GSTZ1 expression among K carrier haplotypes in Whites to the linkage disequilibrium between the K or A allele from the G>A SNP (rs7975), within the promoter G>A-1002 SNP (rs7160195) A allele. There is no linkage disequilibrium between these two polymorphisms in African-Americans.


CONCLUSIONS
We conclude that the lower expression of GSTZ1 in Whites who possess the K carrier haplotype results in lower enzymatic activity and slower metabolism of DCA, compared with those who possess the non-K carrier haplotype. These results further define safe, genetics-based dosing regimens for chronic DCA administration.
aDepartment of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy bDepartment of Medicinal Chemistry, College of Pharmacy cDepartment of Medicine, College of Medicine dDepartment of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA eDepartment of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Taimour Y
TY
Langaee
Guo
G
Zhong
Wenjun
W
Li
Issam
I
Hamadeh
Mohamed Hassan M
MH
Solayman
Caitrin W
CW
McDonough
Peter W
PW
Stacpoole
Margaret O
MO
James
D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics; D002648:Child; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008239:Lysine / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics
D002264:Carboxylic Acids; D003999:Dichloroacetic Acid; C407705:GSTZ1 protein, human; D005982:Glutathione Transferase; D008239:Lysine