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.

Figure 1

Glutathione-dependant metabolism of trichloroethylene (TCE). Glutathione S-transferase (GST), S-(1,2-dichlorovinyl)glutathione (DCVG), γ-glutamyl transpeptidase (GGT), S-(1,2-dichlorovinyl)-L-cysteine (DCVC), flavin-containing monooxygenase 3 (FMO3), S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS), N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (N-AcDCVC), Cytochrome P450 3A1/2 (CYP3A1/2), N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (N-AcDCVCS), chlorothioketene (CTK) and its hydrolysis product chloroketene (CK), and 2-chlorothionoacetyl chloride (2-CTA) and its hydrolysis product 2-chloroacetyl chloride (2-CA). Adapted from [92] with permission of the American Chemical Society.

Figure 2

The reaction between DCVCS and thiol-containing molecules results in the formation of adducts and cross-links. DCVCS contains an α,β-unsaturated moiety allowing it to act as a Michael acceptor, forming a covalent bond with the thiol and and subsequently losing HCl by trans-elimination. Adapted from [82] with permission of the American Chemical Society.

Figure 3

Structures of DCVCS, N-AcDCVCS and N-biotinyl-DCVCS (NB-DCVCS).

Figure 4

NB-DCVCS (●) and DCVCS diastereomers I (▼) and II (■) exhibit half-lives in the same order of magnitude in the presence of GSH. (3:10 molar ratio of sulfoxide to GSH incubated at pH 7.4, 37°C). Adapted from [92] with permission of the American Chemical Society.