Dietary diacetylene falcarindiol induces phase 2 drug-metabolizing enzymes and blocks carbon tetrachloride-induced hepatotoxicity in mice through suppression of lipid peroxidation

Abstract

Falcarindiol is a diacetylenic natural product containing unique carbon-carbon triple bonds. Mice were orally administrated falcarindiol (100 mg/kg), and drug-metabolizing and antioxidant enzymes were monitored in several tissues of mice. Treatment with falcarindiol was found to increase glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 activities in liver, small intestine, kidney, and lung. No changes were observed in cytochrome P450 (CYP) 1A known to activate procarcinogens. Western blot analysis revealed that various GST subunits including GSTA4, which plays an important role in the detoxification of alkenals produced from lipid peroxides, were induced in liver, small intestine, and kidney of falcarindiol-treated mice. Additionally, we investigated the protective effects of falcarindiol against hepatotoxicity induced by carbon tetrachloride (CCl 4) and the mechanism of its hepatoprotective effect. Pretreatment with falcarindiol prior to the administration of CCl 4 significantly suppressed both an increase in serum alanine transaminase/aspartate transaminase (ALT/AST) activity and an increase in hepatic thiobarbituric acid reactive substance levels without affecting CCl 4-mediated degradation of CYP2E1. Formation of hexanoyl-lysine and 4-hydroxy-2(E)-nonenal-histidine adducts, lipid peroxidation biomarkers, in homogenates from the liver of CCl 4-treated mice was decreased in the group of mice pretreated with falcarindiol. These results suggest that the protective effects of falcarindiol against CCl 4 toxicity might, in part, be explained by anti-lipid peroxidation activity associated with the induction of the GSTs including GSTA4. © 2011 Pharmaceutical Society of Japan.