Ouwerkerk-Mahadevan S, Mulder G J
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, The Netherlands.
Chem Biol Interact. 1998 Apr 24;111-112:163-76. doi: 10.1016/s0009-2797(97)00159-2.
Glutathione (GSH) conjugation plays an important role in (de-)toxification of its substrates in vivo. We have developed inhibitors of GSH conjugation that are active in the rat in vivo which are derived from the structure of GSH conjugates: they contain a backbone of gamma-L-Glu-D-2-aminoadipic acid that is virtually isosteric with the gamma-L-Glu-L-Cys-Gly structure of GSH. In addition, a hydrophobic alkyl group is attached such that it may interact with the H-site of the enzyme. Finally, the carboxyl groups were esterified with alcohols of varying chain length. The results show that all these compounds preferentially inhibit alpha-GST's 1-1 and 2-2, have less effect on mu isoenzymes 3-3 and 4-4, and finally, have little effect on rat theta (G.J. Mulder, S. Ouwerkerk-Mahadevan, Modulation of glutathione conjugation in vivo: How to decrease glutathione conjugation in vivo or in intact cellular systems in vitro, Chem. Biol. Interact. 105 (1997) 17-34) and pi (S. Ouwerkerk-Mahadevan, J.H. van Boom, M.C. Dreef-Tromp, J.H.T.M. Ploemen, D.J. Meyer, G.J. Mulder, Glutathione analogues as novel inhibitors of rat and human glutathione S-transferase isoenzymes, as well as of glutathione conjugation in isolated rat hepatocytes and the rat in vivo, Bioche. J., 308 (1995) 283-290). Several of the compounds inhibit the GSH conjugation of bromsulfophthalein and (S)-2-bromisovalerylurea in hepatocytes, in the situ recirculating rat liver perfusion and in the rat in vivo (after i.v. administration). The most effective compound contains a 2-heptylamine group linked as an amide to the 1-carboxyl group of the aminoadipic acid moiety at the H-site, and an ethyl ester at the 5-carboxylic acid group of aminoadipic acid.
谷胱甘肽（GSH）结合反应在其底物于体内的（去）毒过程中发挥着重要作用。我们已研发出在大鼠体内具有活性的GSH结合反应抑制剂，这些抑制剂源自GSH结合物的结构：它们含有γ-L-谷氨酸-D-2-氨基己二酸主链，该主链与GSH的γ-L-谷氨酸-L-半胱氨酸-甘氨酸结构几乎等电子体。此外，连接有一个疏水烷基，使其可能与酶的H位点相互作用。最后，羧基用不同链长的醇进行酯化。结果表明，所有这些化合物优先抑制α-GST的1-1和2-2，对μ同工酶3-3和4-4的影响较小，最终，对大鼠θ（G.J.穆德，S.欧韦尔克-马哈德万，《体内谷胱甘肽结合反应的调节：如何在体内或体外完整细胞系统中降低谷胱甘肽结合反应》，《化学生物相互作用》105（1997年）17 - 34）和π（S.欧韦尔克-马哈德万，J.H.范布姆，M.C.德里夫-特龙普，J.H.T.M.普洛门，D.J.迈耶，G.J.穆德，《谷胱甘肽类似物作为大鼠和人类谷胱甘肽S-转移酶同工酶以及分离的大鼠肝细胞和大鼠体内谷胱甘肽结合反应的新型抑制剂》，《生物化学杂志》，308（1995年）283 - 290）同工酶几乎没有影响。几种化合物在肝细胞、原位再循环大鼠肝脏灌注以及大鼠体内（静脉注射后）抑制溴磺酞和（S）-2-溴异戊酰脲的GSH结合反应。最有效的化合物含有一个2-庚胺基团，以酰胺形式连接到氨基己二酸部分H位点的1-羧基上，且在氨基己二酸的5-羧酸基团处为乙酯。
