Abstract
Aldehyde dehydrogenases (ALDHs) are the major enzyme superfamily for the aldehyde metabolism. Since the ALDH polymorphism leads to the accumulation of acetaldehyde, we considered that the enhancement of the liver ALDH activity by certain food ingredients could help prevent alcohol-induced chronic diseases. Here, we evaluated the modulating effects of 3-hydroxyphenylacetic acid (OPAC), the major metabolite of quercetin glycosides, on the ALDH activity and acetaldehyde-induced cytotoxicity in the cultured cell models. OPAC significantly enhanced the total ALDH activity not only in mouse hepatoma Hepa1c1c7 cells, but also in human hepatoma HepG2 cells. OPAC significantly increased not only the nuclear level of aryl hydrocarbon receptor (AhR), but also the AhR-dependent reporter gene expression, though not the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent one. The pretreatment of OPAC at the concentration required for the ALDH upregulation completely inhibited the acetaldehyde-induced cytotoxicity. Silencing AhR impaired the resistant effect of OPAC against acetaldehyde. These results strongly suggested that OPAC protects the cells from the acetaldehyde-induced cytotoxicity, mainly through the AhR-dependent and Nrf2-independent enhancement of the total ALDH activity. Our findings suggest that OPAC has a protective potential in hepatocyte models and could offer a new preventive possibility of quercetin glycosides for targeting alcohol-induced chronic diseases.
Highlights
Acetaldehyde is the first ethanol metabolite that might mediate various types of ethanol-induced abnormal behaviors and chronic diseases, such as liver diseases, cardiovascular diseases, carcinogenesis, neuropsychic disorders, and addiction [1]
We previously reported that dihydroxyphenylacetic acid (DOPAC), having a catechol moiety, significantly enhanced the total aldehyde dehydrogenase (ALDH) activity [21]
We demonstrated the modulating effects of OPAC on the total ALDH activity in mouse hepatoma Hepa1c1c7 cells, and human hepatoma HepG2 cells (Figure 1)
Summary
Acetaldehyde is the first ethanol metabolite that might mediate various types of ethanol-induced abnormal behaviors and chronic diseases, such as liver diseases, cardiovascular diseases, carcinogenesis, neuropsychic disorders, and addiction [1]. Due to its electrophilic nature, acetaldehyde can directly modify proteins, lipids, and DNA to form covalent conjugates [2]. These conjugates might influence cellular homeostasis and survival through protein structure alteration and/or DNA damage. Among the 19 ALDH family enzymes, ALDH class-2 (ALDH2), a mitochondrial enzyme highly expressed in the liver, plays a major role in the acetaldehyde metabolism into nontoxic acetic acid [3]. In addition to ALDH2, ALDH class-1A1 (ALDH1A1), a cytosolic enzyme highly expressed in the liver, contributes to the acetaldehyde metabolism [4]. ALDH class-3A1 (ALDH3A1), another cytosolic enzyme in the liver, might assist ALDH2 in the ethanol metabolism, even though it selectively oxidized aromatic and medium-chain aldehydes [5]. It is quite plausible that the enhancement of the liver ALDH activities by intake of certain food ingredients could help prevent alcohol-intolerant individuals with a low ALDH activity from experiencing the alcohol-induced abnormal reaction, and chronic diseases
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