Cellular and plasma thiol-containing nucleophiles (Thiol nucleophiles)

Cellular and plasma thiol-containing nucleophiles comprise a broad class of endogenous molecules characterized by reactive sulfhydryl (-SH) groups, including small molecules like glutathione (GSH) and cysteine, as well as proteins such as human serum albumin. Their primary biological role is the maintenance of redox homeostasis and the protection of cellular components from oxidative stress and electrophilic insult (Townsend et al., 2003, PubMed: 12654468). In pharmacology, these thiols function as a critical detoxification system; for example, glutathione conjugates with the reactive acetaminophen metabolite NAPQI to prevent hepatic necrosis (StatPearls, 2023). However, these nucleophiles also pose a challenge in oncology, as elevated intracellular thiol levels can neutralize electrophilic chemotherapeutic agents like cisplatin before they reach their genomic targets, leading to drug resistance (Kuppusamy et al., 2002, PubMed: 12422171). While not a single therapeutic target, modulating the levels of these thiols—such as using N-acetylcysteine to replenish them or buthionine sulfoximine to deplete them—is a significant strategy in managing toxicity and enhancing drug efficacy (Montero et al., 2018, PubMed: 30149525).

Other names

Endogenous thiolsSulfhydryl-containing nucleophilesNon-protein thiolsProtein-bound thiolsThiol-containing scavengers

These molecules act as nucleophilic scavengers that undergo covalent conjugation with electrophilic drugs or reactive metabolites, typically mediated by glutathione S-transferases or through spontaneous chemical reaction, leading to drug inactivation and excretion.