TY - JOUR
T1 - Differential activation and inhibition of different forms of rat liver glutathione S-transferase by the herbicides 2,4-dichlorophenoxyacetate (2,4-D) and 2,4,5-trichlorophenoxyacetate (2,4,5-T)
AU - Vessey, Donald A.
AU - Boyer, Thomas D.
N1 - Funding Information:
The authors acknowledge the expert technical assistance of Neil Saley. This work was supported by the Veterans Administration, the National Institutes of Health (Grants AM19212 and GM31555), and the Liver Center, University of California.
PY - 1984/5
Y1 - 1984/5
N2 - The predominant forms of the dimeric enzyme glutathione S-transferase were purified from rat liver. Forms YbY′b and YbYb (also known as forms C and A, respectively) could be almost completely inhibited by 2,4-dichlorophenoxyacetate (2,4-D). Half-maximal inhibition was obtained at 0.5 mm 2,4-D. Inhibition was seen even at extrapolated infinite concentrations of both substrates for YbYb but not YbY′b. These same forms could also be inhibited 70 to 80% by 2,4,5-trichlorophenoxyacetate (2,4,5-T) with half maximal inhibition occurring at 0.2 mm. Glutathione S-transferase from YaYa was maximally inhibited by 72 and 30%, respectively, by 2,4-D and 2,4,5-T. The 30% inhibition of YaYa caused by 2,4,5-T was shown to reduce the nearly complete inhibition caused by a previously characterized inhibitor, namely bile acids. This suggests competition for a common binding site on the enzyme. In contrast to the above results, it was found that form YcYc (also termed AA) was activated 2.7-fold by 2,4,5-T and 1.4-fold by 2,4-D. This activation could be blocked by chenodeoxycholate which, by itself, did not affect the activity of the enzyme. The effects of 2,4,5-T and 2,4-D on the heterodimer YaYc (also termed form B) were intermediate between their effects on YaYa and YcYc, suggesting that each subunit contributes its unique property to the heterodimer. The microsomal membrane-bound form of glutathione S-transferase was also examined and found to be inhibited by both 2,4-D and 2,4,5-T. However, unlike the inhibitions of soluble forms, 2,4,5-T caused more extensive inhibition than 2,4-D. It is concluded that exposure to 2,4-D and 2,4,5-T can limit the ability of glutathione S-transferase forms YbYb and YbY′b to metabolize electrophilic toxins. This capacity to potentiate the toxicity of certain electrophiles indicates a need to study the effect of herbicides on glutathione S-transferases from human tissues.
AB - The predominant forms of the dimeric enzyme glutathione S-transferase were purified from rat liver. Forms YbY′b and YbYb (also known as forms C and A, respectively) could be almost completely inhibited by 2,4-dichlorophenoxyacetate (2,4-D). Half-maximal inhibition was obtained at 0.5 mm 2,4-D. Inhibition was seen even at extrapolated infinite concentrations of both substrates for YbYb but not YbY′b. These same forms could also be inhibited 70 to 80% by 2,4,5-trichlorophenoxyacetate (2,4,5-T) with half maximal inhibition occurring at 0.2 mm. Glutathione S-transferase from YaYa was maximally inhibited by 72 and 30%, respectively, by 2,4-D and 2,4,5-T. The 30% inhibition of YaYa caused by 2,4,5-T was shown to reduce the nearly complete inhibition caused by a previously characterized inhibitor, namely bile acids. This suggests competition for a common binding site on the enzyme. In contrast to the above results, it was found that form YcYc (also termed AA) was activated 2.7-fold by 2,4,5-T and 1.4-fold by 2,4-D. This activation could be blocked by chenodeoxycholate which, by itself, did not affect the activity of the enzyme. The effects of 2,4,5-T and 2,4-D on the heterodimer YaYc (also termed form B) were intermediate between their effects on YaYa and YcYc, suggesting that each subunit contributes its unique property to the heterodimer. The microsomal membrane-bound form of glutathione S-transferase was also examined and found to be inhibited by both 2,4-D and 2,4,5-T. However, unlike the inhibitions of soluble forms, 2,4,5-T caused more extensive inhibition than 2,4-D. It is concluded that exposure to 2,4-D and 2,4,5-T can limit the ability of glutathione S-transferase forms YbYb and YbY′b to metabolize electrophilic toxins. This capacity to potentiate the toxicity of certain electrophiles indicates a need to study the effect of herbicides on glutathione S-transferases from human tissues.
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U2 - 10.1016/0041-008X(84)90101-7
DO - 10.1016/0041-008X(84)90101-7
M3 - Article
C2 - 6719464
AN - SCOPUS:0021252349
SN - 0041-008X
VL - 73
SP - 492
EP - 499
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 3
ER -