Tissue distribution of cytosolic beta-elimination reactions of selenocysteine Se-conjugates in rat and human.
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, beta-elimination of these compounds by beta-lyase enzymes into corresponding selenols, pyruvate and ammonia is thought to be critical. This study describes in vitro beta-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 beta-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 beta-elimination, hepatic beta-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 beta-lyase data. The results showed that hepatic beta-lyase activities were 4-25-fold lower than the corresponding renal beta-lyase activities. Hepatic beta-elimination of the substrates appeared to be exclusively catalyzed by the pyridoxal 5'-phosphate-dependent beta-lyase enzyme kynureninase. Studies performed with human hepatic cytosols of three individuals showed that hepatic beta-lyase activity was 2-5-fold higher when compared with the previously obtained human renal activity. Significant correlation was obtained between human hepatic beta-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 beta-elimination and specific beta-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.
Department of Pharmacochemistry, Division of Molecular Toxicology, Leiden/Amsterdam Center for Drug Research (LACDR), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Martijn
M
Rooseboom
Nico P E
NP
Vermeulen
Ed J
EJ
Groot
Jan N M
JN
Commandeur
D000818:Animals; D002852:Chromatography, Ion Exchange; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008190:Lyases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity; D016566:Organoselenium Compounds / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017279:Selenocysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
D016566:Organoselenium Compounds; D017279:Selenocysteine; C047601:S-(2-chloro-1,1,2-trifluoroethyl)cysteine; D006867:Hydrolases; C021480:kynureninase; D008190:Lyases; D003545:Cysteine