The influence of human GSTZ1 gene haplotype variations on GSTZ1 expression.
Pharmacogenet Genomics
; 25(5): 239-45, 2015 May.
Article
em En
| MEDLINE
| ID: mdl-25738370
ABSTRACT
BACKGROUND/OBJECTIVES:
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. MATERIALS ANDMETHODS:
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.CONCLUSION:
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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Inativação Metabólica
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Ácido Dicloroacético
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Glutationa Transferase
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Fígado
Limite:
Adolescent
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Adult
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Aged
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Aged80
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Child
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Humans
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Middle aged
Idioma:
En
Revista:
Pharmacogenet Genomics
Assunto da revista:
FARMACOLOGIA
/
GENETICA MEDICA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Egito