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Chloride Modulates GSTZ1 Haplotype‐dependent Inactivation by Dichloroacetate
Author(s) -
Li Wenjun,
Gu Yuan,
Langaee Taimour,
Hines Ronald N.,
Stacpoole Peter W.,
James Margaret O.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.813.2
Dichloroacetate (DCA) is being investigated for treatment of congenital lactic acidosis and cancer. DCA inactivates its own metabolizing enzyme glutathione transferase Z1 (GSTZ1). Three nonsynonymous SNPs (E32K, G42R and T82M) result in five known human GSTZ1 haplotypes: EGT, KGT, EGM, KGM and KRT. Individuals with KRT/KRT and KRT/EGM haplotypes exhibit markedly delayed plasma DCA clearance after repeated doses compared with EGT homo‐ or heterozygous individuals. However liver cytosol from subjects homo‐ or heterozygous for KRT have 3‐fold higher GSTZ1 activity with DCA than does cytosol from subjects with other haplotypes at a given level of GSTZ1 protein expression. To investigate this discrepancy, we examined DCA‐induced inactivation of GSTZ1 in human liver cytosol. Chloride protected GSTZ1 from DCA inactivation in a Cl − concentration‐ and GSTZ1 haplotype‐dependent manner. After 2 hr incubation with 0.5 mM DCA, 50% protection of cytosolic GSTZ1 required 12.3 ± 2.7 mM Cl − (n=3) from EGT/EGT subjects compared to 33.6 ± 2.3 mM Cl − from EGT/KRT subjects (n=3). At physiological hepatic Cl − concentration (38 mM), GSTZ1 activity was reduced 47% in EGT/KRT individuals but only 22% in EGT/EGT individuals. Thus, chloride modulation of GSTZ1 inactivation may contribute to haplotype‐dependent DCA pharmacokinetics. Supported in part by the US PHS grants ES07355, GM081344 and ES014617.