1932

Abstract

Several halogenated alkenes are nephrotoxic in rodents. A mechanism for the organ-specific toxicity of these compounds to the kidney has been elucidated. The mechanism involves hepatic glutathione conjugation to dihaloalkenyl or 1,1-difluoroalkyl glutathione -conjugates, which are cleaved by γ-glutamyltransferase and dipeptidases to cysteine -conjugates. Haloalkene-derived cysteine -conjugates may have four fates in the organism: () They may be substrates for renal cysteine conjugate β-lyases, which cleave them to form reactive intermediates identified as thioketenes (chloroalkene-derived -conjugates), thionoacyl halides (fluoroalkene-derived -conjugates not containing bromide), thiiranes, and thiolactones (fluoroalkene-derived -conjugates containing bromine); () cysteine -conjugates may be -acetylated to excretable mercapturic acids; () they may undergo transamination or oxidation to the corresponding 3-mercaptopyruvic acid -conjugate; () finally, oxidation of the sulfur atom in halovinyl cysteine -conjugates and corresponding mercapturic acids forms Michael acceptors and may also represent a bioactivation reaction.

The formation of reactive intermediates by cysteine conjugate β-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.

Loading

Article metrics loading...

/content/journals/10.1146/annurev.pharmtox.38.1.501
1998-04-01
2024-06-13
Loading full text...

Full text loading...

/content/journals/10.1146/annurev.pharmtox.38.1.501
Loading
/content/journals/10.1146/annurev.pharmtox.38.1.501
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error