Glutathione‐Dependent Bioactivation

Abstract

The classical view of the glutathione (GSH) conjugation pathway involves GSH S-transferase (GST)-dependent formation of thioether conjugates between GSH and an electrophilic substrate, processing to yield the corresponding cysteine S-conjugate, which is then converted to an N-acetylcysteine conjugate (or mercapturate). Mercapturates of most GST substrates are rendered more polar and thus readily excreted in urine. In contrast, there is a growing number of GST substrates that, rather than being detoxified, are bioactivated. These substrates include several halogenated solvents, many of which are nephrotoxic because of the tissue distribution of GSH conjugation pathway enzymes and membrane transporters, and prodrugs of certain chemotherapeutic agents. Although the initiating steps are the same regardless of whether the substrate is detoxified or bioactivated, the cysteine conjugate functions as a branch point. Bioactivated cysteine S-conjugates are metabolized in the kidneys by either cysteine conjugate β-lyase or flavin-containing monooxygenase to produce a reactive intermediate.

Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

“…CCBL activity has been detected not only in the kidneys, but in liver and other tissues as well. Only renal, as opposed to extra-renal, CCBL activity is toxicologically important for kidney toxicity because of the tissue localization of plasma membrane transporters and several of the enzymes of the GSH conjugation pathway that determine the distribution of TCE metabolites [109]. The overall β-lyase reaction mechanism is cleavage of a C-S bond to yield a reactive, thioacylating species.…”

“…Membrane transport and inter-organ translocation processes are important determinants of delivery of metabolic intermediates to sites of further metabolism or toxicity, and thus influence tissue distribution and handling of TCE metabolites [109, 141, 142]. These processes play a critical role in target organ specificity of TCE-induced adverse effects.…”

Diverse Roles of Mitochondria in Renal Injury from Environmental Toxicants and Therapeutic Drugs

“…The concept that renal GSH in general and mtGSH in particular can have both critical protective and toxic roles in renal cells was recently reviewed [55]. An important group of environmental pollutants, halogenated alkanes and alkenes, are known to specifically elicit nephrotoxicity by GSH-dependent metabolism in the kidneys, by both enzymes in the renal PT cytoplasm and mitochondria [56,57]. The concept and key data behind the seemingly contradictory role of GSH in bioactivation date back more than 50 years to a set of studies on the metabolism and toxicity of DCVC in liver mitochondria by Parker [58] and Stonard and Parker [59,60].…”

“…Other GSH S-conjugates that enter the renal tubules via glomerular filtration are rapidly degraded by GGT and DP activities on the BBM to release the corresponding cysteine S-conjugate. While some of these cysteine S-conjugates are metabolized to either N-acetyl-L-cysteine-S-conjugates (i.e., mercapturates) in the cytoplasm, some may also be metabolized by one of several cysteine conjugate-beta-lyases (CCBLs) in either the cytoplasm or mitochondria [56,63,64]. These processes are schematically summarized in Figure 8.…”

“…These processes are schematically summarized in Figure 8. A variety of halogenated alkanes and alkenes, including trichloroethylene, perchloroethylene, hexachlorobutadiene, chlorotrifluoroethylene, and tetrafluoroethylene, all undergo conjugation with GSH, catalyzed by GSH S-transferases, to form GSH S-conjugates [56,57]. These GSH S-conjugates are primarily formed in the liver, but they can also form in many other tissues and are directed to the kidneys via interorgan translocation pathways (e.g., enterohepatic and renal-hepatic transfer) [61].…”