期刊
TOXICOLOGY IN VITRO
卷 26, 期 4, 页码 630-635出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2012.02.005
关键词
Inorganic mercury; Methylmercury; Glutathione s-transferase; Polymorphism; Enzyme activity
类别
资金
- Michigan Institute for Clinical and Health Research (MICHR) [UL1RR024986]
- UM School of Public Health
- NIEHS [T32007062]
Nonsynonymous single nucleotide polymorphisms in glutathione s-transferase pi 1 (GSTP1; Ile/Val 105, Ala/Val 114) have been associated with altered toxicant metabolism in epidemiological cohorts. We explored the impact of GSTP1 genotype on enzyme kinetics and heavy metal inhibition in vitro. Four GSTP1 allozymes (105/114: Ile/Ala, Val/Ala, Ile/Val, Val/Val) were expressed in and purified from Escherichia coli. Enzyme activity assays quantifying the rate of glutathione conjugation with 1-chloro-2,4-dinitrobenzene (CDNB) revealed significant differences in kinetic parameters depending on genotype (p < 0.01). Allozymes with Ile105 had better catalytic efficiency and greater affinity for CDNB (mean +/- SEM: Ile105 Ala114 K-m = 0.33 +/- 0.07 mM vs. Val105 Ala114 K-m = 1.15 +/- 0.07 mM). Inhibition of GSTP1 activity by heavy metals was assessed following treatment with mercury (inorganic-HgCl2, methylmercury-MeHg), selenium, cadmium, lead, arsenic, and manganese. All allozymes were inhibited by HgCl2 (IC50 range: 24.1-172 mu M), MeHg (93.9-480 mu M), and selenium (43.7-62.8 mu M). Genotype significantly influenced the potency of mercury with GSTP1 Ile105 Val114 the least sensitive and Val105 Ala114 the most sensitive to inhibition by HgCl2 and MeHg. Overall, genotype of two nonsynonymous polymorphisms in GSTP1 influenced enzyme kinetics pertaining to an electrophilic substrate and inhibition by two mercury species. Published by Elsevier Ltd.
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