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

M. MONTALTO DE MECCA; G.D. CASTRO; J.A. CASTRO

ARCHIVES OF TOXICOLOGY.

Springer-Verlag

Año: 1993 vol. 67 p. 547 - 551

0340-5761

Dithiotreitol (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 dithiotreitol tetraacetate (DTT-Ac) which is less toxic and chemically stable, and we provided GLC/MS evidencie 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.