Role of reactive metabolites in the circulation in extrahepatic toxicity.
BACKGROUND
Reactive metabolite-mediated toxicity is frequently limited to the organ where the electrophilic metabolites are generated. Some reactive metabolites, however, might have the ability to translocate from their site of formation. This suggests that for these reactive metabolites, investigations into the role of organs other than the one directly affected could be relevant to understanding the mechanism of toxicity.


METHODS
The authors discuss the physiological and biochemical factors that can enable reactive metabolites to cause toxicity in an organ distal from the site of generation. Furthermore, the authors present a case study which describes studies that demonstrate that S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS) and N-acetyl-S-(1,2-dichlorovinyl-L-cysteine sulfoxide (N-AcDCVCS), reactive metabolites of the known trichloroethylene metabolites S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (N-AcDCVC), are generated in the liver and translocate through the circulation to the kidney to cause nephrotoxicity.


CONCLUSIONS
The ability of reactive metabolites to translocate could be important to consider when investigating mechanisms of toxicity. A mechanistic approach, similar to the one described for DCVCS and N-AcDCVCS, could be useful in determining the role of circulating reactive metabolites in extrahepatic toxicity of drugs and other chemicals. If this is the case, intervention strategies that would not otherwise be feasible might be effective for reducing extrahepatic toxicity.
University of Wisconsin-Madison, School of Veterinary Medicine, Department of Comparative Biosciences and Molecular and Environmental Toxicology Center, Madison, WI 53706, USA.
Roy M
RM
Irving
Adnan A
AA
Elfarra
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000633:toxicity; D003545:Cysteine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014241:Trichloroethylene / Q000097:blood / Q000378:metabolism / Q000633:toxicity
C534676:S-(1,2-dichlorovinyl)-L-cysteine sulfoxide; C049705:S-1,2-dichlorovinyl-N-acetylcysteine; D014241:Trichloroethylene; C039961:S-(1,2-dichlorovinyl)cysteine; D003545:Cysteine; D000111:Acetylcysteine