Evaluation of the kinetics of β-elimination reactions of selenocysteine Se-conjugates in human renal cytosol:: possible implications for the use as kidney selective prodrugs

作     者：Rooseboom, M Vermeulen, NPE Andreadou, I Commandeur, JNM 

作者机构：Free Univ Amsterdam Dept Pharmacochem Div Mol Toxicol Leiden Amsterdam Ctr Drug Res NL-1081 HV Amsterdam Netherlands 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：2000年第294卷第2期

页      面：762-769页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：胞质溶胶/酶学 肾/酶学 动力学 裂合酶类/代谢 药物前体/药代动力学 大鼠 Wistar 硒代胱氨酸/类似物和衍生物 硒代胱氨酸/化学合成 硒代胱氨酸/药代动力学 构效关系 底物特异性 老年人 动物 人类 男(雄)性 中年人 大鼠 

摘      要：This study was performed to evaluate whether selenocysteine Se-conjugates are substrates for human cysteine conjugate beta-lyase enzymes. By testing kidney cytosols of three different humans, we studied interindividual differences in beta-lyase enzymes in humans. A series of 22 selenocysteine Se-conjugates were tested in rat and human kidney cytosols to compare their ability to form selenol compounds by beta-elimination. All compounds appeared to be good substrates for rat and human cysteine conjugate beta-lyase enzymes. The beta-lyase activity toward the selenocysteine Se-conjugates was comparable with those of the known nephrotoxic cysteine S-conjugate S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine in rats and humans. In rat kidney cytosol, between 22- and 877-fold higher beta-elimination rates were observed compared with human kidney cytosol. Significant correlations (P .0001) between three human kidney cytosols in beta-lyase activities were found within the tested series of 22 compounds. Specific beta-lyase activities and intrinsic clearances of beta-elimination reactions ranged up to 3-fold, indicating that there are quantitative rather than qualitative interindividual differences in beta-eliminating enzymes in humans. Furthermore, Se-alkyl selenocysteine conjugates showed a sterically dependent bioactivation to selenol compounds in humans but not in rats. The present study supports the hypothesis that selenocysteine Se-conjugates may be useful as prodrugs to target pharmacologically active selenol compounds (e.g., antitumor or chemoprotective) to the kidney in humans.