Abstract
Living organisms are continuously exposed to xenobiotics. The major phase of enzymatic detoxification in many species is the conjugation of activated xenobiotics to reduced glutathione (GSH) catalyzed by the glutathione-S-transferase (GST). It has been reported that some compounds, once transformed into glutathione S-conjugates, enter the mercapturic acid pathway whose end products are highly reactive and toxic for the cell responsible for their production. The cytotoxicity of these GSH conjugates depends essentially on GST and gamma-glutamyl transferases (γGT), the enzymes which initiate the mercapturic acid synthesis pathway. Numerous studies support the view that the expression of GST and γGT in cancer cells represents an important factor in the appearance of a more aggressive and resistant phenotype. High levels of tumor GST and γGT expression were employed to selectively target tumor with GST- or γGT-activated drugs. This strategy, explored over the last two decades, has recently been successful using GST-activated nitrogen mustard (TLK286) and γGT-activated arsenic-based (GSAO and Darinaparsin) prodrugs confirming the potential of GSH-conjugates as anticancer drugs.
Highlights
Glutathione (GSH) plays a myriad of roles in the body
This review explores the importance of the mercapturic acid pathway and the potential of intra-tumor activation of old and recently discovered chemotherapeutics
This review describes the enzymes involved in drug activation in the order they participate along the mercapturic acid pathway, GST, gamma-glutamyl transferase (γGT), and β-lyase
Summary
Glutathione (GSH) plays a myriad of roles in the body. It is a major cellular antioxidant, involved in defense against oxidative stress and redox signaling. GSH and enzymes of the mercapturic acid pathway play a role in resistance to many chemotherapeutic drugs. The newly formed cysteinylglycine S-conjugates are further processed by dipeptidases/aminopeptidases to remove the glycyl group and produce cysteine S-conjugates These compounds re-enter the cell via various transporters including organic anion transport polypeptides and cystine/cysteine importers (Hinchman et al, 1998; Budy et al, 2006; Dilda et al, 2008, 2009; Garnier et al, 2014). N -acetyl transferases create mercapturic acid versions of the xenobiotics which are generally more polar and more water soluble than the parental compound. Instead of acetylation, some compounds can be converted by cysteine S-conjugate β-lyase to produce an unstable and highly reactive thiol
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