Danielson U H, Mannervik B
Department of Biochemistry, Arrhenius Laboratory, University of Stockholm, Sweden.
Biochem J. 1988 Mar 15;250(3):705-11. doi: 10.1042/bj2500705.
Under standard assay conditions, with 1-chloro-2,4-dinitrobenzene (CDNB) as electrophilic substrate, rat glutathione transferase 4-4 is strongly inhibited (I50 = 1 microM) by indomethacin. No other glutathione transferase investigated is significantly inhibited by micromolar concentrations of indomethacin. Paradoxically, the strong inhibition of glutathione transferase 4-4 was dependent on high (millimolar) concentrations of CDNB; at low concentrations of this substrate or with other substrates the effect of indomethacin on the enzyme was similar to the moderate inhibition noted for other glutathione transferases. In general, the inhibition of glutathione transferases can be explained by a random-order sequential mechanism, in which indomethacin acts as a competitive inhibitor with respect to the electrophilic substrate. In the specific case of glutathione transferase 4-4 with CDNB as substrate, indomethacin binds to enzyme-CDNB and enzyme-CDNB-GSH complexes with an even greater affinity than to the corresponding complexes lacking CDNB. Under presumed physiological conditions with low concentrations of electrophilic substrates, indomethacin is not specific for glutathione transferase 4-4 and may inhibit all forms of glutathione transferase.
在标准测定条件下，以1-氯-2,4-二硝基苯（CDNB）作为亲电底物时，大鼠谷胱甘肽转移酶4-4受到吲哚美辛的强烈抑制（I50 = 1微摩尔）。所研究的其他谷胱甘肽转移酶均未被微摩尔浓度的吲哚美辛显著抑制。矛盾的是，谷胱甘肽转移酶4-4的强烈抑制取决于高（毫摩尔）浓度的CDNB；在该底物低浓度或使用其他底物时，吲哚美辛对该酶的作用类似于对其他谷胱甘肽转移酶所观察到的中度抑制。一般来说，谷胱甘肽转移酶的抑制作用可用随机顺序的序列机制来解释，其中吲哚美辛相对于亲电底物起竞争性抑制剂的作用。在以CDNB为底物的谷胱甘肽转移酶4-4的特定情况下，吲哚美辛与酶 - CDNB和酶 - CDNB - GSH复合物的结合亲和力甚至比对缺乏CDNB的相应复合物更高。在假定的亲电底物低浓度的生理条件下，吲哚美辛对谷胱甘肽转移酶4-4不具有特异性，可能会抑制所有形式的谷胱甘肽转移酶。
