Dietary Diacetylene Falcarindiol Induces Phase 2 Drug-Metabolizing Enzymes and Blocks Carbon Tetrachloride-Induced Hepatotoxicity in Mice through Suppression of Lipid Peroxidation

Abstract

Falcarindiol (heptadeca-1,9(Z)-diene-4,6-diyne-3,8-diol) is a diacetylenic natural compound commonly occurring in the families Apiaceae and Araliaceae and is found in the edible parts of plants commonly used for food in the Apiaceae family such as carrot, celery, and parsnip. 1) Falcarindiol has been shown to have antibacterial activity [2][3][4] and an anti-inflammatory effect. 5,6) These beneficial effects occur at non-toxic concentrations and thus represent pharmacologically useful properties. Recently, we firstly found that falcarindiol has the ability to induce phase 2 drug-metabolizing enzymes (DMEs) and antioxidant enzymes in a liver-derived cell line and protect such cells against cytotoxicity caused by electrophilic stress.7) Moreover, we elucidated the mechanism of phase 2 DME induction by falcarindiol at both cellular and molecular levels and emphasized that a conjugated diacetylene in the chemical structure of falcarindiol played an important role in the induction mechanism. 8)Phase 2 DMEs, such as glutathione S-transferase (GST) and UDP-glucuronosyltransferase (UGT), and quinone-reducing enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) are involved in the detoxification of carcinogens and function to facilitate their elimination. Therefore, induction of phase 2 DMEs and NQO1 is an effective mechanism for protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by chemical compounds. A wide variety of dietary and synthetic compounds that function as inducers of those DMEs have been shown to exert a chemopreventive effect. For instance, sulforaphane, an isothiocyanate compound found in broccoli, is known as a potent GST and NQO1 inducer and has been reported to suppress carcinogen-induced tumorigenesis in rodent organs, including colon, skin, and stomach. 9-11)The expression of GST and NQO1 is up-regulated by nuclear factor-E2-related factor 2 (Nrf2) binding to the antioxidant response element (ARE), a cis-acting sequence located in the 5Ј-flanking region of these genes.12,13) Most GST and NQO1 inducers, including falcarindiol and sulforaphane, interact with critical cysteines in Kelch-like ECH-associated protein 1 (Keap1) through alkylation, allowing Nrf2 to escape proteasomal degradation and to accumulate in the nucleus.8,14-17) Accumulated Nrf2 activates the expression of multiple categories of genes, including genes for phase 2 DME, anti-inflammatory responses, and molecular chaperones as well as stress response genes such as heme oxygenase-1 (HO-1). 18,19) Thus, the Keap1/Nrf2/ARE signaling pathway plays a central role in cytoprotection against various stress conditions. Based on amino acid sequence similarities, seven classes (alpha, mu, pi, sigma, theta, omega, and zeta) of cytosolic GSTs are recognized in mammalian species. 20) GSTs catalyze the nucleophilic addition of the thiol of glutathione (GSH) to a variety of electrophiles. Metabolites after glutathionylation are more hydrophilic and normally less reactive. They are readily excreted in bile and/or urine as con...

Dietary Coleus forskohlii extract generates dose‐related hepatotoxicity in mice

“…GST isozymes also exhibit GSH peroxidase activity and catalyse the reduction of hydroperoxides of fatty acids, and phospholipids (Frova, ). Previous studies have demonstrated that induction of the GSTs protected against CCl4‐induced hepatotoxicity in mice by catalysing the decomposition of lipid hydroperoxides generated from oxidative damage of cellular lipid molecules (Ohnuma et al ., ; Yang et al ., ). Also there is a clear manifestation of excessive formation of hepatic lipid peroxidation associated with the decline in the levels of antioxidant enzymes including GST (Fukao et al ., ).…”

Dietary Regulation of Keap1/Nrf2/ARE Pathway: Focus on Plant-Derived Compounds and Trace Minerals

“…Falcarindiol upregulated catalase, GST, NQO1 and HO-1 in rat hepatocytes and effectively protected against menadione-induced oxidative stress [95]. In vivo , falcarindiol acts systemically to upregulate NQO1 and HO-1 in key tissues facing detoxification challenges: liver, kidney, lung, and small intestine [96]. …”

Autophagy contributes to falcarindiol-induced cell death in breast cancer cells with enhanced endoplasmic reticulum stress

“…FAD has been shown to have anti-inflammation, antibacterial, and anticancer activities, as well as protective effects against hepatotoxicity. These benefits were achieved at non-toxic concentrations and thus represent pharmacologically useful properties [6,7,8,9]. The anticancer activity of FAD was described in some cancer cells [10,11].…”