A Major Intestinal Catabolite of Quercetin Glycosides, 3-Hydroxyphenylacetic Acid, Protects the Hepatocytes from the Acetaldehyde-Induced Cytotoxicity through the Enhancement of the Total Aldehyde Dehydrogenase Activity

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.

Gut Microbiota Influences the Photoperiod Effects on Proanthocyanidins Bioavailability in Diet‐Induced Obese Rats

“…This microbial-derived metabolite has showed antihypertensive and anti-cytotoxic effects, depending on the gut dysbiosis condition. [72,73] Therefore, the levels of these two interesting metabolites can be affected by the photoperiod via gut microbiota composition, as it can be influenced by the photoperiod. [23,36] Interestingly, these effects were significantly less prominent when treating with ABX.…”

Downregulation of aryl hydrocarbon receptor-mediated gene expression by Fraglide-1, a PPARγ agonist isolated from aromatic vinegar

“…Establishment and validation of the XRE-NanoLuc luciferase reporter assay using the XRE-NLuc::HaCaT cell line To determine the potential effect of FG1 on the xenobiotic response caused by AhR, we generated a HaCaT human keratinocyte cell line stably expressing NanoLuc luciferase under three XRE motifs (CACGC) (Fig. 2a: vector map; 2b: cell image) 23 . The e cacy of this cell line was veri ed using established XRE activators (AhR ligands), such as 6-formylindolo (3, 2-b), carbazole (FICZ), indirubin (IND), 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), and indole-3-carbinol (I3C) 24 .…”

Aldehyde Dehydrogenases as Potential Targets for Ethanol-Related Diseases

“…3,4-Dihydroxyphenylacetic acid (DOPAC) and 3-hydroxyphenylacetic acid (OPAC) are the major intestinal catabolites of the quercetin glycosides produced by the gut microbiota 23,25) . We demonstrated that DOPAC and OPAC each significantly protected the cells from the acetaldehyde-induced cytotoxicity with the enhanced total ALDH activity through the transcriptional regulation 26,27) . On the other hand, there is a significant difference in the antioxidant activities between DOPAC and OPAC, even though their chemical structures are quite similar to each other.…”