Comparative Study on the Bioactivation Mechanisms and Cytotoxicity of Te-Phenyl-L-tellurocysteine, Se-Phenyl-L-selenocysteine, and S-
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- 作者：Martijn Rooseboom ; Nico P. E. Vermeulen ; Fatma Durgut ; and Jan N. M. Commandeur
- 刊名：Chemical Research in Toxicology
- 出版年：2002
- 出版时间：December 2002
- 年：2002
- 卷：15
- 期：12
- 页码：1610 - 1618
- 全文大小：195K
- 年卷期：v.15,no.12(December 2002)
- ISSN：1520-5010
文摘
Tellurium compounds are effective antioxidants and chemoprotectors, even more active thantheir selenium and sulfur analogues. In addition to these properties, some selenium compounds,such as selenocysteine Se-conjugates, possess significant chemopreventive and antitumoractivities, and selenol metabolites are considered as active species. In the present study, wehave synthesized Te-phenyl-L-tellurocysteine and evaluated its bioactivation and cytotoxicity.The activities of this compound were compared with those of the corresponding selenium andsulfur analogues. Te-Phenyl-L-tellurocysteine is bioactivated into its corresponding tellurol,as detected by GC-MS, by cysteine conjugate 
-lyase and amino acid oxidase, analogously towhat has been shown previously for Se-phenyl-L-selenocysteine. The rate of -elimination mayreflect the bond strength of the corresponding C-S, C-Se, and C-Te bond. Bioactivation ofTe-phenyl-L-tellurocysteine and its selenium and sulfur analogues by oxidative enzymes wasevaluated by measuring NADPH-dependent activation of hepatic mGST and inhibition ofEROD. Te-Phenyl-L-tellurocysteine and Se-phenyl-L-selenocysteine displayed strong and time-dependent mGST activation, while S-phenyl-L-cysteine resulted in no significant activation.Te-Phenyl-L-tellurocysteine was also a strong inhibitor of EROD activity. In addition to ERODinhibition, Te-phenyl-L-tellurocysteine was the strongest inhibitor of several human cytochromeP450 isoenzymes followed by Se-phenyl-L-selenocysteine, while S-phenyl-L-cysteine was theweakest inhibitor. Interestingly, Te-phenyl-L-tellurocysteine selectively inhibited cytochromeP450 1A1 directly, which is, for example, responsible for the activation of several procarcinogens.Preliminary cytotoxicity studies with Te-phenyl-L-tellurocysteine in freshly isolated rathepatocytes showed a time-dependent depletion of GSH and LDH leakage comparable withthe relatively nontoxic drug paracetamol, while the selenium and sulfur analogues werenontoxic toward rat hepatocytes. In conclusion, because the chemopreventive and antitumoractivities of selenium compounds are thought to be mediated via their selenol metabolites andtellurium compounds might be even more active than selenium compounds, tellurocysteineTe-conjugates might be an interesting novel class of prodrugs for the formation of biologicallyactive tellurols.
-lyase and amino acid oxidase, analogously towhat has been shown previously for Se-phenyl-L-selenocysteine. The rate of -elimination mayreflect the bond strength of the corresponding C-S, C-Se, and C-Te bond. Bioactivation ofTe-phenyl-L-tellurocysteine and its selenium and sulfur analogues by oxidative enzymes wasevaluated by measuring NADPH-dependent activation of hepatic mGST and inhibition ofEROD. Te-Phenyl-L-tellurocysteine and Se-phenyl-L-selenocysteine displayed strong and time-dependent mGST activation, while S-phenyl-L-cysteine resulted in no significant activation.Te-Phenyl-L-tellurocysteine was also a strong inhibitor of EROD activity. In addition to ERODinhibition, Te-phenyl-L-tellurocysteine was the strongest inhibitor of several human cytochromeP450 isoenzymes followed by Se-phenyl-L-selenocysteine, while S-phenyl-L-cysteine was theweakest inhibitor. Interestingly, Te-phenyl-L-tellurocysteine selectively inhibited cytochromeP450 1A1 directly, which is, for example, responsible for the activation of several procarcinogens.Preliminary cytotoxicity studies with Te-phenyl-L-tellurocysteine in freshly isolated rathepatocytes showed a time-dependent depletion of GSH and LDH leakage comparable withthe relatively nontoxic drug paracetamol, while the selenium and sulfur analogues werenontoxic toward rat hepatocytes. In conclusion, because the chemopreventive and antitumoractivities of selenium compounds are thought to be mediated via their selenol metabolites andtellurium compounds might be even more active than selenium compounds, tellurocysteineTe-conjugates might be an interesting novel class of prodrugs for the formation of biologicallyactive tellurols.