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Organ-specific carcinogenicity of haloalkenes mediated by glutathione conjugation
1Department of Toxicology, University of Würzburg, Germany. dekant@toxi.uni-wuerzburg.de
Abstract:
Several halogenated alkenes are nephrotoxic in rodents. A mechanism for the organ-specific toxicity to the kidney for these compounds has been elucidated. The mechanism involves hepatic glutathione conjugation to dihaloalkenyl or 1,1-difluoroalkyl glutathione S-conjugates, which are cleaved by gamma-glutamyltransferase and dipeptidases to cysteine S-conjugates. Haloalkene-derived cysteine S-conjugates are substrates for renal cysteine conjugate beta-lyases, which cleave them to form reactive intermediates identified as thioketenes (from chloroalkene-derived S-conjugates) or thionoacyl halides (from 1,1-difluoroalkyl S-conjugates). Alternatively, cysteine S-conjugates may be N-acetylated to excretable mercapturic acids. The formation of reactive intermediates by cysteine-conjugate beta-lyase may play a role in the target-organ toxicity and in the possible renal tumorigenicity of several chlorinated olefins widely used in many chemical processes.
Insights
Halogenated alkenes cause kidney damage through a specific metabolic pathway. This process generates reactive intermediates that may lead to organ toxicity and potential kidney tumors.
Area of Science:
- Toxicology
- Metabolism
- Organic Chemistry
Background:
- Halogenated alkenes are known nephrotoxins in rodent models.
- Understanding the mechanism of organ-specific kidney toxicity is crucial for risk assessment.
Purpose of the Study:
- To elucidate the mechanism of nephrotoxicity induced by halogenated alkenes.
- To identify the reactive intermediates involved in kidney damage and potential tumorigenicity.
Main Methods:
- Hepatic glutathione conjugation of halogenated alkenes.
- Enzymatic cleavage of S-conjugates by gamma-glutamyltransferase and dipeptidases.
- Substrate analysis of renal cysteine conjugate beta-lyases.
Main Results:
- Halogenated alkenes are metabolized to cysteine S-conjugates in the liver.
- Renal cysteine conjugate beta-lyases cleave these conjugates to form reactive thioketenes or thionoacyl halides.
- N-acetylation leads to excretable mercapturic acids, representing an alternative pathway.
Conclusions:
- The formation of reactive intermediates by cysteine-conjugate beta-lyase is a key mechanism for halogenated alkene nephrotoxicity.
- These reactive intermediates may contribute to target-organ toxicity and potential renal tumorigenicity.
- The findings are relevant to widely used chlorinated olefins in chemical processes.