Oleanolic acid and the synthetic triterpenoids CDDO, CDDO-Me, and CDDO-Im induce antioxidant processes

Abstract

Oleanolic acid (OA) is a triterpenoid compound, which is a natural ingredient in some Chinese herbal medicines used for the treatment of hepatitis. OA has previously been shown in our laboratory to diminish the hepatotoxicity of chemicals such as carbon tetrachloride, acetaminophen, and cadmium. In order to develop even more effective chemicals, derivatives of OA were synthesized, namely CDDO, CDDO-Me, and CDDO-Im. In the present study, we sought to determine genetic markers by which these chemicals might protect the liver against hepatotoxicants, as well as to compare the efficacy of these chemicals to activate these genetic markers. Genetic screening of mice treated with one of the triterpenoids (CDDO-Im), resulted in induction of various genes in the liver, such as heme-oxygenase-1 (HO-1), NAPDH quinone oxidoreductase-1, epoxide hydrolase-1, glutathione-S-transferases, and glutamate-cysteine ligase catalytic subunit. This suggests that these triterpenoids induce genes that protect against oxidative stress. To further determine the potency and efficacy of these triterpenoids, livers were removed 6 hours after a single administration of the triterpenoids at various dosages, total RNA extracted, and the expression of one antioxidant enzyme, HO-1 was quantified. All four triterpenoids increased the expression of HO-1, with OA being the least effective, CDDO and CDDO-Me being intermediate, and CDDO-Im being the most effective. In conclusion, the novel compounds CDDO, CDDO-Me, and CDDO-Im have shown significant promise for the prevention of oxidative stress by upregulation of a variety of antioxidant genes.