Tissue distribution of cytosolic β-elimination reactions of selenocysteine Se-conjugates in rat and human

Abstract

Selenocysteine Se-conjugates (e.g. methylselenocysteine) have been shown to be potent chemopreventive and chemoprotective agents, and inducers of apoptosis. Although the mechanism of action remains to be elucidated, β-elimination of these compounds by β-lyase enzymes into corresponding selenols, pyruvate and ammonia is thought to be critical. This study describes in vitro β-lyase activity in nine rat organs using three selenocysteine Se-conjugates and S-(2-chloro-1,1,2-trifluoroethyl)- l-cysteine. For all substrates the highest β-elimination rates were found in kidney, followed by liver, while brain, spleen, heart, large and small intestine, thyroid and lung were of minor importance. Since liver plays an important role in β-elimination, hepatic β-lyase activity was extensively studied using 23 selenocysteine Se-conjugates and S-(2-chloro-1,1,2-trifluoroethyl)- l-cysteine and was compared with previously obtained renal β-lyase data. The results showed that hepatic β-lyase activities were 4–25-fold lower than the corresponding renal β-lyase activities. Hepatic β-elimination of the substrates appeared to be exclusively catalyzed by the pyridoxal 5′-phosphate-dependent β-lyase enzyme kynureninase. Studies performed with human hepatic cytosols of three individuals showed that hepatic β-lyase activity was 2–5-fold higher when compared with the previously obtained human renal activity. Significant correlation was obtained between human hepatic β-lyase activities of three individuals. The relevance of this data for using SeCys-conjugates as chemopreventive and a chemoprotective agent is discussed. Based on the large differences in organ-selective β-elimination and specific β-lyase activity between rat and humans, the rat might not be a good model to investigate nephrotoxicity of cysteine S-conjugates, and chemoprevention and chemoprotection of SeCys-conjugates in man.