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Introduction Alcohol, i.e., ethanol, is absorbed into the blood from the stomach to the small intestine, then distributed throughout the body. The metabolism of alcohol converting to acetic DIG-11-dUTP basically involves two enzymes; alcohol dehydrogenase converting ethanol to acetaldehyde and aldehyde dehydrogenase (ALDH) catalyzing the conversion from acetaldehyde to its corresponding acids (Matysiak-Budnik et al., 1996). Nineteen genes have already been identified as members of the human ALDH family (Vasiliou and Nebert, 2005). Among the ALDH family enzymes, ALDH2 is a mitochondrial enzyme ubiquitously expressed with the highest level in the liver and plays a pivotal role in the acetaldehyde detoxification (Yoshida et al., 1998). In Asian countries, about 40% of the people have the mutation of ALDH2, which is called ALDH2*2. The acetaldehyde-metabolizing ability of the ALDH2*2 individuals is only about 15% as efficient as that of wild type individuals. This mutation leads to the accumulation of acetaldehyde which causes significant damage to the liver and serious abnormal reactions of the body like vasodilation and facial flushing (Goedde et al., 1980), (Agarwal et al., 1981), (Xiao et al., 1995). ALDH polymorphism may also result in an increased vulnerability to developing cancer (Wang et al., 2014). In addition to ALDH2, a cytosolic ALDH, ALDH1A1, has also been reported to express at a high level in the liver tissue of humans and play a major role in the acetaldehyde metabolism (Lind et al., 2008). Another cytosolic ALDH, ALDH3A1, has been suggested to assist ALDH2 in the metabolism of acetaldehyde and ethanol in vivo, even though it exhibits a selective activity for oxidation of aromatic and medium-chain aldehydes (Chen et al., 2015). Therefore, the strategy for enhancement of the liver ALDH activities by the administration of food phytochemicals is most likely to prevent humans, who are intolerant to alcohol with a low ALDH activity, from not only an alcohol-induced abnormal reaction, but also chronic diseases including cancer. A previous study demonstrated that the ALDH activity could be enhanced by the activation of the Kelch like-ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/antioxidant response element (ARE) pathway (Nguyen et al., 2000), (Kensler et al., 2007), (Baird and Dinkova-Kostova, 2011). Nrf2 is the key factor to modulate the phase 2 drug-metabolizing enzyme activity, including glutathione S-transferases (GSTs), glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1) (Nakamura and Miyoshi, 2010). Evaluation of 20 inducers of the phase 2 enzymes belonging to various chemical classes, including isothiocyanates (ITCs), triterpenoids, flavonoids and stilbenes, demonstrated that their induction potencies of ALDH were closely correlated with those for the NQO1 induction (Ushida and Talalay, 2013). ITCs, mainly derived from cruciferous vegetables, such as broccoli, wasabi (Japanese horseradish) and watercress, are highly effective for cancer chemoprevention in vitro and in vivo (Nakamura and Miyoshi, 2010). We previously demonstrated that benzyl ITC (BITC), an ingredient in papaya (Nakamura et al., 2007), induces phase 2 drug-metabolizing enzymes such as GSTs (Nakamura et al., 2000). BITC inhibits cell proliferation by inducing cell cycle arrest or apoptosis in hepatocytes (Nakamura et al., 2002), T lymphocytes (Miyoshi et al., 2004), colon fibroblasts (Miyoshi et al., 2007), cervical epithelial cells (Miyoshi et al., 2008), renal proximal tubular cells (Abe et al., 2012), and colorectal cancer cells (Abe et al., 2014). In addition, BITC reduces inflammatory responses in macrophages (Murakami et al., 2003) and the allergy-related cytokine expression in basophil cells (Tang et al., 2015).
Materials and methods
Results
Discussion In the present study, we demonstrated that BITC is a potential enhancer of the total ALDH enzyme activity. BITC dose-dependently enhanced not only the total ALDH activity, but also the cytoplasmic/mitochondrial ALDH activity for 24 h (Fig. 1). Simultaneously, the BITC treatments increased the gene expression of not only mitochondrial ALDH, ALDH2, but also cytosolic ALDHs, ALDH1A1, and ALDH3A1 (Fig. 2). These results suggested that BITC enhanced the total ALDH activity through a transcriptional regulation. Ushida et al. reported that other ITCs, such as sulforaphane, erucin, ilberin and 4-(rhamnopyranosyloxy)-benzyl isothiocyanate, have potencies for induction of the ALDH activity between 2 and 20 μM (Ushida and Talalay, 2013), whereas phenethyl ITC was reported to be a potential inhibitor of the ALDH activity (Lindros et al., 1995). A food component, alpha-lipoic acid, has been found to significantly increase the ALDH2 activity in isolated rat heart mitochondria at a concentration of more than 100 μM (Wenzel et al., 2007). Four flavonoids from Echinosophora koreensis also have a positive effect on the ALDH activity in vivo (Choi et al., 2009). Compared to the other ALDH enhancers, BITC is one of the most potent food components for increasing the total ALDH activity.