Inhibition of human glutathione S-transferase omega by tocopherol succinate.
Glutathione S-transferases (GSTs) are a family of multifunctional enzymes that are present in all living organisms. Their main function is the detoxification of electrophilic compounds. Glutathione conjugation is the major detoxification pathway available to the organism to trap toxic substances. Based on their substrate specificity, sequence structure, catalytic activity, immunogenicity and sensitivity to inhibitors, the mammalian GSTs form seven distinct classes termed alpha, mu, pi, sigma, theta, zeta, and new class of human GSTs designated omega. Human GST omega 1-1 (hGSTO1-1) is identical to human monomethylarsenic acid (MMAV), the rate-limiting enzyme for biotransformation of inorganic arsenic. It is expressed in a wide range of human tissues, including brain. Several studies have indicated a role for an Omega-class GST gene in the early onset of both Alzheimer's and Parkinson's diseases, and it is possible that hGSTO1-1 may be involved in the modulation of the activity of interleukin-1 (IL-1) which play a major role in a wide range of inflammatory disease. Compounds that target IL-1 production are being investigated. We found that (+)-alpha-tocopherol succinate inhibited the reduction monomethylarsenate (MMAV) and dimethylarsenate (DMAV) in a concentration-dependent manner with an IC(50) of 4 and 3 microM, respectively. The kinetics indicated an uncompetitive inhibition of the MMA(V) and DMA(V) reducing activity of hGSTO1-1.
Sampayo-Reyes
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A
División de Farmacología y Toxicología, Centro de Investigacíon Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey Nuevo León, México. adriana.sampayo@biomedicas.net
Zakharyan
R A
RA
D001152:Arsenicals; D004791:Enzyme Inhibitors; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010084:Oxidation-Reduction; D011994:Recombinant Proteins; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D001152:Arsenicals; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D014810:Vitamin E; C490476:GSTO1 protein, human; D005982:Glutathione Transferase; D024505:Tocopherols