Glutathione-dependent detoxification of α-oxoaldehydes by the glyoxalase system:: involvement in disease mechanisms and antiproliferative activity of glyoxalase I inhibitors

The glyoxalase system is a metabolic pathway that catalyses the detoxification of alpha-oxoaldehydes RCOCHO to corresponding aldonic acids RCH(OH)CO2H. It thereby protects cells from alpha-oxoaldehyde-mediated formation of advanced glycation endproducts (AGEs). It is comprised of two enzymes, glyoxalase I and glyoxalase II, and a catalytic amount of reduced glutathione (GSH) as cofactor. It is present in the cytosol of cells of mammals and most micro-organisms. Physiological substrates of the glyoxalase system are: glyoxal-fonned from lipid peroxidation and glycation reactions, methylglyoxal-formed from triosephosphates, ketone body metabolism and threonine catabolism, and 4,5-dioxovalerate-formed from 5-aminolevulinate and oc-ketoglutarate. alpha-Oxoaldehydes react with guanyl residues in DNA and RNA, and with cysteine, lysine and arginine residues in proteins. The modification of DNA induces mutagenesis and apoptosis. The modification of proteins leads to protein degradation and activation of a cytokine-mediated immune response in monocytes and macrophages. An acute decrease in cellular GSH, as occurs in oxidative stress, leads to decreased in situ activity of glyoxalase I, accumulation of alpha-oxoaldehydes and cytotoxicity. Chronic exposure to increased methylglyoxal concentration occurs in diabetes mellitus and is associated with chronic clinical complications (retinopathy, neuropathy, nephropathy). The alpha-oxoaldehyde scavenger Pimagedine is under clinical evaluation for prevention of diabetic complications. Pharmacological inhibition of glyoxalase I induces an acute increase in methylglyoxal concentration, growth arrest and apoptosis. Glyoxalase I inhibitors are under development as antitumour and antimalarial agents. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.