GLUTATHIONE-DEPENDENT BIOACTIVATION OF XENOBIOTICS

Glutathione conjugation has been identified as an important detoxicati on reaction. However, in recent years several glutathione-dependent bi oactivation reactions have been identified. Current knowledge on the m echanisms and the possible biological importance of these reactions ar e discussed. 1. Dichloromethane is metabolized by glutathione conjugat ion to formaldehyde via S-(chloromethyl)glutathione. Both compounds ar e reactive intermediates and may be responsible for the dichloromethan e-induced tumorigenesis in sensitive species. 2. Vicinal dihaloalkanes are transformed by glutathione S-transferase-catalyzed reactions to m utagenic and nephrotoxic S-(2-haloethyl)glutathione S-conjugates. Elec trophilic episulphonium ions are the ultimate reactive intermediates f ormed. 3. Several polychlorinated alkenes are bioactivated in a comple x, glutathione-dependent pathway. The first step is hepatic glutathion e S-conjugate formation followed by cleavage to the corresponding cyst eine S-conjugates, and, after translocation to the kidney, metabolism by renal cysteine conjugate beta-lyase. Beta-lyase-dependent metabolis m of halovinyl cysteine S-conjugates yields electrophilic thioketenes, whose covalent binding to cellular macromolecules is responsible for the observed toxicity of the parent compounds. 4. Finally, hepatic glu tathione conjugate formation with hydroquinones and amino-phenols yiel ds conjugates that are directed to gamma-glutamyltransferase-rich tiss ues, such as the kidney, where they undergo alkylation or redox cyclin g reactions, or both, that cause organ-selective damage.