תגובות שלב II: צימוד גלוטתיון ויצירת חומצה מרקפטורית

Glutathione is a tripeptide composed of three amino acids: glutamic acid, cysteine, and glycine. It plays a pivotal role in detoxification through glutathione conjugation, a phase II biotransformation reaction. Glutathione's high nucleophilicity and cellular concentration make it immediately available for conjugating xenobiotics and drugs, enhancing their water solubility for excretion.

Glutathione conjugation is distinctive because it does not require coenzyme or substrate activation, unlike other phase II reactions such as glucuronidation or sulfation. Glutathione's high nucleophilicity enables direct attack on electrophilic centers of xenobiotics. Additionally, glutathione conjugates are relatively stable and highly water-soluble, making them effective biomarkers for drug or toxin exposure.

Glutathione conjugation occurs when glutathione's thiol group attacks the electrophilic center of a xenobiotic via nucleophilic substitution or addition reactions. This creates a covalent bond between glutathione's sulfur atom and the compound's electrophilic center. Glutathione S-transferases catalyze this reaction, which can occur with various functional groups including epoxides, halides, and nitro groups.

Mercapturic acids are metabolic products formed when glutathione conjugates are further metabolized by losing glutamine and glycine. These resulting acids are more stable and highly water-soluble than their glutathione conjugate precursors, enabling easy excretion from the body. This transformation represents a critical step in completing the detoxification and elimination of xenobiotics.

Acetaminophen undergoes glutathione conjugation to form a reactive metabolite that can induce liver toxicity if not promptly conjugated with glutathione. This conjugation prevents hepatotoxicity by rendering the reactive intermediate less harmful and more readily excretable. The process demonstrates how glutathione conjugation effectively detoxifies potentially harmful drug metabolites.

Glutathione S-transferases (GSTs) are the enzymes that catalyze glutathione conjugation reactions. These enzymes facilitate the nucleophilic attack of glutathione's thiol group on electrophilic centers of drugs or metabolites. GSTs enable the reaction to proceed efficiently via nucleophilic substitution or addition, depending on the chemical structure of the target compound.

Glutathione conjugation increases a compound's water solubility through covalent attachment of glutathione, which is highly hydrophilic. This enhanced solubility allows conjugates and their mercapturic acid metabolites to be readily eliminated through urine or bile. The process transforms lipophilic xenobiotics into water-soluble products that the body can efficiently excrete.