Antioxidative stress therapy with dithiothreitol tetraacetate. I. Protection against carbon tetrachloride induced liver necrosis.

Abstract

Dithiothreitol (DTT) is known to prevent or even reverse several deleterious effects of radiation or of chemical agents operating via free radical and oxidative stress. However, its use has been hampered by its chemical instability and toxic properties. In this work, we synthesized and characterized dithiothreitol tetraacetate (DTT-Ac) which is less toxic and chemically stable, and we provided GLC/MS evidence that it is able to rapidly generate fully deacetylated DTT in liver after its administration to rats. Treatment with DTT-Ac simultaneously with CCl4 or 3 h after the hepatotoxin was able to significantly prevent the CCl4-induced liver necrosis at 24 h after poisoning. DTT-Ac administration was able to significantly reduce the intensity of the covalent binding of CCl4 reactive metabolites to microsomal lipids (CB), but it did not prevent the CCl4-induced initiation of a lipid peroxidation (LP) process as evidenced by diene hyperconjugation of microsomal lipids. Results suggest that DTT-Ac protective effects might be due to its in vivo conversion to DTT which in turn would decrease the intensity of CB via different potential mechanisms to be explored. Protection cannot be attributed to decreases in levels of CCl4 reaching the liver or to chain breaking effects on LP.