Role of reactive metabolites in the circulation in extrahepatic toxicity

Abstract

Introduction 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. Areas covered 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. Expert Opinion 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.

Rutin ameliorates oxidative stress and preserves hepatic and renal functions following exposure to cadmium and ethanol

“…Because of their locations, structures and involvement in processing and removal of foreign compounds and waste products, the kidney and liver are vulnerable to toxic effects of Cd accumulation, EtOH biotransformation and environmental chemicals (Lock and Reed 1998 ; Jurczuk et al. 2004 ; Irving and Elfarra 2012 ).…”

Effects of co-exposure to atrazine and ethanol on the oxidative damage of kidney and liver in Wistar rats

“…Simultaneous exposures to environmental chemicals in the natural as well as in the occupational setting mimic real human scenario, and individual effects of chemicals have been reported to be significantly influenced by mixture interactions [35]. The liver is usually the first target of ingested compounds before they get into the body fluids and thus exposed to high concentrations of these chemicals [36]. This intense role of the kidney in the processing of foreign chemicals and homeostasis makes it vulnerable to the adverse effects of xenobiotics and reactive metabolites-induced toxicity [36].…”

“…The liver is usually the first target of ingested compounds before they get into the body fluids and thus exposed to high concentrations of these chemicals [36]. This intense role of the kidney in the processing of foreign chemicals and homeostasis makes it vulnerable to the adverse effects of xenobiotics and reactive metabolites-induced toxicity [36]. Therefore, whenever xenobiotics that are metabolize in the liver and processed in the kidney, are taken by an individual who is also chronically consuming EtoH, the combined effects of these agents on the hepatic and renal health has to be considered [37,38].…”

Effects of antioxidants on xenobiotics-induced nephrotoxicity

“…An important function of these enzymes is the metabolism of endogenous as well as exogenous compounds. The renal proximal tubular cells are the main target for metabolism of chemical induced nephrotoxicity (5). Biotransformation of chemical compounds does not fundamentally result in substrate detoxification.…”