ACRYLIC-ACID INDUCES THE GLUTATHIONE-INDEPENDENT MITOCHONDRIAL PERMEABILITY TRANSITION IN-VITRO

Acrylic acid (AA) is used widely in the synthesis of esters essential in the production of paints, adhesives, plastics, and coatings, The mi nimal systemic toxicity of AA is attributed to its rapid oxidation to acetyl-CoA and CO2 via the vitamin B-12-independent beta-oxidation pat hway. This oxidation is localized to the mitochondria and preliminary evidence suggests a possible inhibition of mitochondrial metabolism by acrylic acid. The purpose of this investigation was to evaluate wheth er AA interferes with mitochondrial bioenergetics in vitro. Incubation of isolated rat liver mitochondria with AA resulted in a dose-depende nt induction of the mitochondrial permeability transition (MPT). This was evidenced by an increased sensitivity to calcium-induced stimulati on of state 4 oxygen consumption, depolarization of membrane potential , and swelling, all of which were prevented by preincubating the mitoc hondria with cyclosporine A, a potent and specific inhibitor of the mi tochondrial permeability transition pore, Both N-ethylmaleimide (NEM) and dithiothreitol (DTT) showed only partial protection against induct ion of the MPT by AA, Associated with the induction of the MPT by AA w as the loss of mitochondrial glutathione (GSH), which was due to efflu x from the matrix rather than oxidation to GSSG. Cyclosporine A, by in hibiting the permeability transition, prevented the AA-induced loss of mitochondrial GSH. In conclusion, AA increases the sensitivity of iso lated mitochondria in vitro to the calcium-dependent induction of the MPT, Although the molecular mechanism has yet to be defined, it does n ot appear to be related to the oxidation of critical thiols. (C) 1998 Society of Toxicology.