Detoxification activity of bioactive food compounds against ethanol‐induced injuries and hangover symptoms: A review

Abstract Alcohol drinking is a popular activity among adolescents in many countries, largely due to its pleasant, relaxing effects. As a major concern, ethanol consumption put the drinkers at risk of nutrients' deficiency due to the disordered eating, anorexia, and malabsorption of nutrients. Moreover, alcohol drinking may lead to the development of hangover symptoms including diarrhea, thirsty, fatigue, and oxidative stress. A broad range of functional food components with antioxidant and/or anti‐inflammatory properties including pectin, aloe vera polysaccharides, chito‐oligosaccharides, and other herbal components have been explored due to their detoxification effects against ethanol. The underlying anti‐hangover mechanisms include reducing the intestinal absorption of ethanol or its metabolites, increasing the activity of ethanol metabolizing enzymes, development of fatty acid β‐oxidation in mitochondria, inhibition of inflammatory response, blocking the target receptors of ethanol in the body, and possession of antioxidant activity under the oxidative stress developed by ethanol consumption. Therefore, the development of bioactive food‐based therapeutic formula can assist clinicians and also drinkers in the alleviation of alcohol side effects.

the varying results of numerous studies, owing to the alcohol's harmful and long-lasting physical, mental, chemical, and behavioral implications, which cause a substantial financial burden on healthcare systems, most governments have deemed alcohol unsafe and taken steps to ensure that convenient access to alcohol is limited in line with the WHO action plan 2013-2020 (Burton & Sheron, 2018;Moslemi et al., 2020;Rekve et al., 2019).
The scientific literature indicates that alcohol metabolism can have a significant effect on the absorption of essential nutrients.
Alcohol, once ingested into the body, is mainly absorbed in the upper intestinal tract by diffusion, promoting gastrointestinal inflammation (Kamran et al., 2020;Thomson et al., 2017).The alcohol-induced intestinal inflammation may be a potential contributor to organ failure, such as chronic liver disease, or immune dysfunctions.Acute alcohol ingestion is often associated with the development of combined physical and mental symptoms such as dizziness, headache, fatigue, and muscle pain; these symptoms are known as hangover effects (Saether et al., 2019;Verster et al., 2010).
Alcohol metabolism appears to depend on a number of criteria such as race/ethnicity, sex, age, disease status, nutritional status, amount of the consumed alcohol, and duration of alcohol exposure (Cederbaum, 2012;Rajendram & Preedy, 2005).Given the high reactivity of ethanol to agents in the environment, it can be easily absorbed, mainly in the upper intestinal tract, and then is distributed to different organs, where it can impair several biological processes (Figure 1).
The home-based detoxification of drinkers with hangover symptoms without a need for hospitalization is critical to prevent organ damage or unintended death.Several studies have shown that natural food components and medicinal extracts with antioxidant properties can relieve the severe symptoms of alcohol hangovers (Cui et al., 2014;Czech & Seki, 2020;Srinivasan et al., 2019;Uto-Kondo et al., 2018, 2020).The underlying detoxification mechanisms of natural food extracts in suppressing hangover symptoms are not well documented.In response to this gap in the literature, this paper aims to critically overview a broad range of food supplements and functional food components with antioxidant and/or anti-inflammatory properties that can alleviate ethanol disorders and induce ethanol detoxification effects.

| PATHWAYS OF E THANOL ME TABOLIS M
In humans, ingested alcohol is primarily absorbed from the stomach and the small intestine.The liver is the major organ responsible for metabolizing up to 90% of ingested alcohol.There are two main pathways that enable metabolization of ethanol: alcohol dehydrogenase (ADH) and cytochrome P4502E1 (CYP2E1).ADH catalyzes the oxidation of F I G U R E 1 A summary of potential long-term health effects of excessive alcohol drinking on some main organs.ethanol to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase (ALDH) (Figure 2).In addition, catalase oxidation in the third pathway especially in the brain and when oxidative stress develops (Jiang et al., 2020;Wilson & Matschinsky, 2020).
ADH and ALDH, two NAD + -dependent enzymes, use the conversion of the cofactor nicotinamide adenine dinucleotide (NAD + ) to its reduced form (NADH).In the first reaction, ethanol loses a proton (H + ), and a hydride ion (H − ) is transferred from the ethanol to NAD + to reduce it to NADH, resulting in an enhanced NADH/NAD + ratio.During excessive alcohol consumption, CYP2E1 accompanies ADH in ethanol metabolism.In this catalytic cycle, a significant amount of reactive oxygen species (ROS) is produced, inducing an oxidative stress (Cederbaum, 2010;Guengerich & Avadhani, 2018;Kawaratani et al., 2013;Mohn & Johnson, 2015).Most of these oxidative pathways occur in the liver.Thus, the liver is the organ most vulnerable to alcoholism (Haynuk & Sheremeta, 2019).

| ALLE VIATION OF E THANOL-INDUCED INJ URIE S BY FOOD SUPPLEMENTATI ON
Increasing evidence suggested that excessive alcohol consumption could affect the availability of nutrients, particularly when alcoholinduced vomiting, degenerated intestinal epithelium, anorexia, or diarrhea occur (Bode & Bode, 2003;Seitz & Suter, 2002).Research has identified a number of possible explanations for the co-occurrence of alcohol use and disordered eating.Alcohol, once consumed, suppresses the appetite in the alcoholics by elevating the secretion of tumor necrosis factorα (TNFα) and leptin (the satiety hormone secreted by adipose tissues).This is followed by upregulation of the secondary inflammatory factors including interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) by TNFα, which further suppresses appetite (Kamran et al., 2020).Followed by diarrhea induced by ethanol, the lower sodium concertation leads to reduced activity of sodium-potassium ATPase and glutathione/glucose cotransporters on the intestinal cell surface (Butts et al., 2019).Moreover, excessive alcohol prevents protein synthesis in the small intestine: Contractile proteins are less likely to be synthesized in the gastrointestinal (GI) tract of alcohol drinkers in which peristaltic movements and transition time of food are adversely affected (Thomson et al., 2017).These malnutrition and malabsorption are exacerbated in the drinkers when metabolism of essential nutrients is affected.For example, folate is an important vitamin for the development of fetal nervous system and its absorption is largely affected by alcohol consumption.Persson et al. (2013) reported that high folate intake could be helpful in ameliorating alcohol side effects and preventing alcohol-associated liver diseases.Folate deficiency can lead to acute ethanol-induced diarrhea because it facilitates an increase in cyclic adenosine monophosphate concentrations by stimulating and activating adenylate cyclase in the intestinal mucosa (Bode & Bode, 2003).Carnitine plays an essential role in the transfer of fatty acids into the mitochondria for their metabolism (Figure 3).Considering the high prevalence of malnutrition and malabsorption in heavy drinkers of alcohol, their bodies often suffer from the depletion of carnitine and other micronutrients such as lysine and methionine (precursors of carnitine).Given the crucial role of carnitine in facilitating fatty acid metabolism, its reduced levels can significantly affect hepatic fatty acid beta-oxidation in alcoholics.
Therefore, carnitine supplementation or consumption of animal protein may be helpful in prevention of ethanol-induced liver damages (Wilson & Matschinsky, 2020).
Vitamin D deficiency due to less exposure of the drinkers to sunlight and disordered enzymatic metabolism of the vitamin (Gonzalez-Reimers et al., 2017), calcium deficiency as a result of vitamin D depletion (Rajendram & Preedy, 2005), B-group vitamin deficiency due to their malabsorption (Miyazaki et al., 2012;Rajendram & Preedy, 2005;Seitz & Mueller, 2014;Subramanya et al., 2010), and vitamin A and vitamin E deficiencies in response to the oxidative stress after alcohol intake (Gonzalez-Reimers et al., 2014) are of other nutritional problems after alcoholism which can be ameliorated by food supplementation.

| ALLE VIATION OF E THANOL-INDUCED INJ URIE S AND HANGOVER SYMP TOMS BY B I OAC TIVE FOOD COMP OUNDS
Alcohol hangover refers to the combination of mental and physical symptoms when increased alcohol metabolism and formation of metabolites in the body lead to reduced blood alcohol concentrations.The hangover symptoms may often last for 24 h after alcohol consumption (Verster et al., 2010).Several hangover treatments have been proposed to reduce the sudden rise in inflammatory mediators' concentrations after heavy drinking (Khan et al., 2019;Shati & Elsaid, 2009;Yan et al., 2014).If alcohol is consumed along with the food, it contributes to the formation of free radicals and oxidative conditions) or iron-enriched food (which acts as a prooxidant) (Hyun et al., 2021;Niemela, 2001).However, one potential treatment can be the use of dietary bioactive agents to eliminate or minimize the development of next-day hangover symptoms.These bioactive compounds facilitate alcohol detoxification by stimulating the activity of the enzymes involved in alcohol metabolism, serving as strong antioxidants to suppress toxicity and ethanol-induced oxidative stress, and reduce the chance of alcohol uptake in the GI tract (Lu et al., 2020;Ozkol et al., 2017;Srinivasan et al., 2019).As reported, the hangover symptoms arisen from alcohol consumption are mainly driven by acetaldehyde.Importantly, the bioactive components could be specifically served as functional ingredients exhibiting positive effects on ALDH activity, thereby promoting more conversion of acetaldehyde to acetic acid.Indeed, this can greatly help in the immediate clearance of acetaldehyde and ethanol from the body (Srinivasan et al., 2019).In the next section, we review the scientific mechanisms of some selected food components that have exhibited significant anti-hangover effects through detoxification of alcohol metabolites (Table 1).

| Pectin
Pectin is a multifunctional and non-digestive biopolymer, popularly known as dietary fiber, which serves a wide range of roles including antimicrobial activities, carrier for nutraceutical and drug delivery, TA B L E 1 A summary of anti-hangover food compounds and the underlying mechanisms for alleviation of ethanol side effects in the drinkers.and binders in biological systems (Cheraghali et al., 2018;Moslemi et al., 2014Moslemi et al., , 2018)).The most attractive property of pectin lies in its manifold affinity to ethanol, which allows it to neutralize and detoxify ethanol's metabolites and alleviate ethanol-induced disorders (Sheremeta & Haynuk, 2018).

Food compound Anti-hangover mechanism References
Ethanol intake interferes in fat metabolism and may lead to hypercholesterolemia (Ayaz & Alnahdi, 2018).Research has shown that oral administration of pectin at concentration of 0.2 g per 100 g of body weight in ethanol-intoxicated rats resulted in a significant decrease in blood cholesterol, TG, and total lipid compared to control groups (Sheremeta & Haynuk, 2018).Pectin was also found to induce detoxification in mice after direct administration of ethanol into their stomachs.When the mice ingested pectin 30 min after ethanol administration, most of the pectin-treated animals seemed to show no ethanol in their blood after testing with a gas chromatograph (Haynuk & Sheremeta, 2018).Pectin's partial ethanol neutralization and detoxification are associated with its carboxyl groups, which tend to interact with ethanol's hydroxyl groups.As a result of this interaction and the formation of a pectin complex, the viscosity of the intestinal fluid increases; this hinders the absorption of ethanol.The changes in viscosity of intestinal fluid adjacent to the brush border caused by pectin affect the epithelial absorption process, hindering the uptake of ethanol or ethanol-derived metabolites across the intestine (Figure 4).
The viscosifying effects of dietary fiber ultimately reduce lipogenesis in the liver, leading to lower lipid accumulation.Moreover, pectin can interact with gastrointestinal components (bile salts) and the surrounding lipids in the intestine, which may induce their rapid loss into the feces.Thus, the binding of bile acids by pectin in the intestine contributes to more conversion of cholesterol to bile acids in the liver (Moslemi, 2021;Zhu, Hou, et al., 2017;Zhu, Sun, et al., 2017).

| Aloe vera polysaccharides
Aloe vera is a perennial plant belonging to the Aloeaceae family.Aloe vera polysaccharides (AVPs) were shown to possess a rapid detoxification effect in the presence of reactive ethanol-induced metabolites.
The role of pectin in enhancing the viscosity of intestinal mucus and its inhibitory impacts on absorption of ethanol or ethanolderived metabolites.These inhibitory effects ultimately reduce lipogenesis in the liver.
For example, Cui et al. found that unpleasant hangover symptoms associated with ethanol intoxication were significantly reduced in mice fed with AVPs.The authors observed a better profile of antioxidant system in the serum of ethanol-intoxicated mice fed with AVPs, with lower levels of total cholesterol and TG compared to control groups.
In addition, mice fed with AVPs had lower accumulations of hepatic TG compared to those not fed with AVPs.AVP-treated groups of mice also presented an increase in the specific activity of superoxide dismutase and glutathione levels, and AVPs reduced levels of the inflammatory mediators such as TNFα.AVPs also increased the expression of AMPK and PPARα, which are involved in fatty acid beta-oxidation in the liver.This led to accelerating fat degradation, resulting in a suppression of alcohol's intoxicating effects (Cui et al., 2014).The AVPs also effectively prevented the adsorption of bacterial LPS on the intestine, leading to their decreased presence in the blood; this makes it a potential candidate for treating alcohol-induced endotoxemia.
Although the influence of AVPs on ethanol-induced metabolites remains unclear, the authors hypothesized that AVPs could exert a protective effect against alcohol-induced liver injury by scavenging free radicals and inhibiting inflammatory responses (Kumar et al., 2019;Sierra-Garcia et al., 2014).

| Chito-oligosaccharides
Chito-oligosaccharides (COSs) are hydrolyzed products of chitosan that have been proven to be effective in alleviating ethanol-induced hangover symptoms.Mice orally administered COSs (200 mg/kg) showed lower blood acetaldehyde levels compared to the control group.This could be due to the COS-induced increased activity of ALDH (with no significant changes in mRNA expression), which is largely involved in detoxification of ethanol-derived metabolites.The COSs may facilitate the attachment of ALDH to the acetaldehydebinding sites.It was also suggested that the individual administration of COSs increased the expression and phosphorylation activity of AMPK.Activated AMPK stimulated the formation of NAD + , which is required for ALDH enzymatic activity.AMPK activation is also followed by the phosphorylation of its substrate, acetyl-CoA carboxylase 1, which plays an essential role in regulating fatty acid beta-oxidation (Cho et al., 2010).Importantly, COSs could suppress oxidative stress by increasing the activity of glutathione peroxidase.

| Herbal medicine
Medicinal plants are appealing in toxicological science due to remediation of several toxicity-induced diseases.They are popular around the world because of their least side effects in people compared to chemical medicines.Camellia sinensis is of popular medicinal plants in the world and its infusion is commonly used especially in Asia.With regard to anti-hangover effect, promising results were observed by its extract in alleviation of tiredness and thirsty in the intoxicated individuals (Hwang & Kim, 2020).Extracts of Houttuynia cordata, Nelumbo nucifera G. leaf, and Camellia sinensis seed had ameliorating effect on hangover symptoms of intoxicated rats in the study of You et al.In their study, blood ethanol and acetaldehyde in the rats treated by herbal extract were lower than their levels in the control group.In addition, the herbal-treated group showed an increased activity of liver ADH and ALDH, which helped in faster clearance of ethanol and acetaldehyde from the body (You et al., 2016) 173.20% for ALDH; Lee, Kim, et al., 2009).Similar study conducted by Noh et al. (2009) found that Dandelion juice could increase the concentrations of plasma ALDH and expression of catalase and glutathione reductase in males aged 24-28 years.Alleviation of hangover symptoms was also studied by Lieb and Schmitt (Lieb & Schmitt, 2020) in healthy adult individuals by administration of a formula containing Malpighia glabra fruit extract, Opuntia ficus indica fruit extract, Ginkgo biloba leaf extract, Salix alba leaf extract, and Zingiber officinale root extract enriched with vitamins and minerals.To understand the detoxification effects of plant extract, a second group delivered a supplement that contained vitamins and minerals in the absence of the plant extracts.In this study, the detoxification effects were significantly observed in the group that received the plant extracts but were not observed in another group supplied by only minerals and vitamins.On the basis of this observation, the authors concluded that restoration of electrolytes and vitamins to the body had no significant effect in alleviation of ethanol hangover symptoms and the main role was governed by the plant extracts presumably through activation of ADH and ALDH enzymes, inhibition of pro-inflammatory mediators, and development of antioxidant activity (Lieb & Schmitt, 2020).

| Minerals
Although Lieb and Schmitt (2020) found that the minerals may confer little or no effect in alleviating the ethanol-induced side effects, their significant effects on repression of post-alcohol symptoms have been reported by other scientists.In this contribution, selenium (Se), zinc (Zn), magnesium (Mg), copper (Cu), and vanadium (V) were reported to deliver the most effects in reducing the ethanolhangover symptoms (Min et al., 2010).Among these, selenium has a leading position to serve as a cofactor of glutathione peroxidase which is important in antioxidant reactions.Other than its role in antioxidant activities, it also contributes to expression of the genes responsible for production of immunomodulatory proteins.In addition, Mn, Cu, and Zn are also cofactors of the antioxidant enzyme of superoxide dismutase.Other minerals such as calcium (Ca), Zn, V, and Cu can also take part in oxidation-reduction reactions (Min et al., 2010).Mn blocks the N-methyl-d-aspartate receptors (NMDRs) in the brain that is a target of ethanol leading to cognitive deficits in intoxicated individuals (Ron & Wang, 2009;Smith et al., 2009).Zn also contributes to NMDR and GABA receptors resulting in prevention of alcohol-induced depression.However, mineral homeostasis is a determinant factor so that their consumption beyond the threshold may have adverse impact (Min et al., 2010).
A recent study found that the highest activity of hepatic ADH and ALDH in mice treated by honey with different origins was observed for the samples containing the highest levels of Zn, Cu, and Fe, and relatively high amount of Mg (Guo et al., 2019).

| Ginseng
Detoxification effects of red ginseng drink (containing 0.32 mg/ mL red ginseng extract) was evaluated by Lee et al.It was found that the individuals who received the dosage of red ginseng drink had lower blood alcohol levels after 30, 45, and 60 min compared with the control group that received water after ethanol intake.The authors concluded that red ginseng possessed a long-term and effective anti-hangover effects associated with their detoxification potential due to the presence of antioxidant compounds that can suppress the oxidative stress developed after alcohol intake in the liver (Lee et al., 2014).In another study, linoleic acid was introduced as a bioactive compound in ginseng to modulate the activity of alcohol metabolism enzymes (Wang et al., 2016).Although it was found that that the presence of antioxidants in ginseng is more likely to relieve ethanol intoxication effects because of the susceptibility of the double bonds in linoleic acid to the oxidative reactions that occurred after ethanol intake (Warner et al., 2017).Similar studies presented a decreased blood alcohol concentration in participants who consumed a dosage of ethanol and fed with a formula containing Hoveni dulcis Thunb extract and ginseng-berry extract (Park et al., 2019;Sharma et al., 2020).This outcome confirmed the detoxification effects of ginseng extract in ethanol-intoxicated individuals.

| Hovenia dulcis tree
Water extracts of oxidated leaf and branch of H. dulcis tree were examined for anti-hangover potential and detoxification activity in mice before ethanol intake.The extracts were found to increase ADH and ALDH activity in the liver in the similar way to other food bioactive ingredients.The mixture of both extracts also increased the expression of ALDH2 (the major isozyme responsible for acetaldehyde clearance) and SOD2 (an antioxidant enzyme responsible for breaking down superoxide radicals) in the liver.Nitration of tyrosine is a side effect reaction that occurs under ethanol drinking and leads to deformation of proteinaceous structures including catalase responsible for alcohol metabolism.Interestingly, tyrosine nitration was suppressed significantly in the mice fed by a mixture of oxidated leaf and branch of H.
dulcis, in which the polyphenol compounds present in the extracts played a great role.The highest anti-nitration effect was related to the extract prepared by branch of H. dulcis tree due to the activity of catechin as the abundant flavonoid.In addition, the antioxidant potency of the extracts could successfully inhibit glutathione depletion in the liver of the treated mice (Je et al., 2021).The favorable activity of H. dulcis extract might also be due to its effect on increased level of IL-10 as anti-inflammatory compound and decreased production of IL-6 as pro-inflammatory agent (Kim et al., 2017).Furthermore, H.
dulcis contains a flavonoid known as dihydromyricetin that able to interact with GABA receptors and block alcohol intoxication by which some hangover symptoms are suppressed (Wang et al., 2016).Similar detoxification role was observed by the administration of theracurmin drink containing H. dulcis fruit stalk and theracurmin (highly bioavailable curcumin) extracts.This bioactive drink could successfully increase GSH level in the ethanol-fed rats by using its antioxidant activity (Kang et al., 2021).Other than functionality of the bioactive compounds naturally present in the plants, their bioprocessing can exacerbate their potential detoxification effects.For example, greater anti-hangover effects were observed for fermented H. dulcis Thunb fruit extract in reduction of blood alcohol and acetaldehyde compared with non-fermented extract (Choi et al., 2014).

| Other food components
In addition to the functional foods and bioactive food compounds mentioned earlier, several other food-based components have been found to alleviate the hangover symptoms of alcoholism with their detoxification effects.It is notable that some of these compounds are commercially available.A liquid-based formula named Oh!K, composed of ginger, green tea, turmeric, and pepper, could successfully diminish post-alcohol disorders in intoxicated drinkers (Sreeraj Gopi et al., 2014).Another herbal formula, with the commercial name of "PartySmart," was found to prevent ethanol-induced hangovers by increasing the activities of ADL and ALDH in the liver, resulting in the rapid breakdown of acetaldehydes (Pordie, 2015).
"DotShot," a product containing curcumin and lemon as its principal ingredients, was also reported to be efficient in the management of alcohol hangover by increasing the activity of ALDH (Harisha, 2018).
The mixture of glutathione-enriched yeast extract and rice embryo/soybean extract fermented by Bacillus subtilis Natto was examined for alleviation of hangover symptoms by Lee et al.In their study, one group of rats was subjected to a 2-week pretreatment by the mixture and another group was fed by the mixture 1 h after ethanol administration.The authors concluded that bioactive compounds including thiamin and Zn present in the mixture inhibited the absorption of ethanol in the intestine or their antioxidant activities prevented the body from oxidative damages and consequent symptoms.In addition, the expression of CYP2E1 was decreased in both groups suggesting less oxidative stress in the extract-treated rats.In addition, increased expression and activity of ADH and ALDH in the liver by the mixture was of great importance (Lee, Song, et al., 2009).
Similarly, the blood concentration of ethanol and acetaldehyde in alcohol-intoxicated rats treated by bioprocessed black rice bran and glutathione-enriched yeast extract were significantly reduced.It was concluded that antioxidant potential of ɤ-oryzanol in the rice bran and the role of cysteine in glutathione (i.e., a tripeptide composed of glutamate-cysteine-glycine) toward acetaldehyde inactivation were important protective factors (Kim et al., 2021).
Increased ADH activity by food sources was also approved in the study of Lee and Bae (2011), through which ADH activity was increased by 63% in vitro in the presence of ethanolic extract of mulberry compared to a commercial detox drink.Similar results with respect to the stimulatory effect of propolis on hepatic ADH and ALDH activity after ethanol administration were reported by Lee and Park (Lee & Park, 2021).Persimmon juice fermented by Lactobacillus species could increase ADH and ALDH activity in vitro owing to the activity of GABA produced by the bacterial fermentation and other bioactive compounds in the fruit (Zhou et al., 2019).
It was reported that GABA may inhibit intestinal absorption of ethanol and stimulate the expression and the activity of alcohol metabolizing enzymes (Boby et al., 2021;Cha et al., 2011).The last effect might be due to the antioxidant activity of GABA (Zhu et al., 2019).
It has been reported that oxidative stress and progress of lipid peroxidation decrease the activity of ALDH and lead to development of hangover symptoms in drinkers (Kim et al., 2018;Min et al., 2010).
Therefore, natural antioxidants in foodstuff have positive effects on ADH and ALDH activity by control of oxidation reactions (Lee, Isse, et al., 2013;Seo et al., 2014).On the other hand, ALDH2 stimulates GABA synthesis from acetate through TCA cycle by which analgesic effect of ethanol is perceived (Jin, Cao, et al., 2021;Jin, Cinar, et al., 2021).Therefore, the development of acetaldehyde metabolism in favor of GABA synthesis is another route in suppression of hangover symptoms.
Protective effects of epigallocatechin-3-gallate (EGCG), the polyphenols from green tea, in alleviating alcohol hangover symptoms have also been approved.Czech and Seki (2020) reported that EGCG may be used as a promising therapy for alcohol-induced disorders.EGCG supplementation in rats can regulate toll-like receptors (TLRs) and has been shown to suppress the elevation of intrahepatic TLRs (TLR2, TLR4, and TLR9) in the Kupffer cells by inducing the production of immunomodulatory cytokines such as interleukin-10 (IL-10) (Liu et al., 2014).Diosmin (Diosmetin-7-O-rutinoside), a naturally occurring citrus flavone, was observed to induce similar preventive effects in the treatment of ethanol-intoxicated rats by alleviating ethanol-induced hepatic and gastric lesions.These beneficial outcomes are partly due to its remarkable antioxidant and antiinflammatory activities, which reduce oxidative stress in the gastric mucosa (Arab et al., 2015).Cuevas et al. found that grapeseed extract could attenuate the development of ethanol-induced gastric ulcerative lesions and MDA levels (Cuevas et al., 2011).the authors recommended against consuming coffee after ethanol ingestion because of its property of prolonging the time needed to clear acetaldehyde from the body as a result of decreased activity of both ADH and ALDH.Interestingly, the authors could not find any correlation between the antioxidant capacity and the activity of ADH and ALDH (Srinivasan et al., 2019).Despite this lack of relationship, the positive impacts of antioxidants in the suppression of oxidative stress after alcohol consumption should not be ignored (Hipolito et al., 2015;Lee, Kim, & Min, 2013;Ozkol et al., 2017;Srinivasan et al., 2019).

| CON CLUS ION
As highlighted throughout this review, ethanol consumption is primarily linked to gastrointestinal malabsorption of micronutrients, in particular water-soluble vitamins, and their deficiencies in the body.Other than food supplementation in compensation for the not-absorbed and/or lost nutrients through ethanol drinking, several dietary food components were identified as detoxifying agent that could influence alcohol metabolism, and thereby potentially alleviate the development of alcohol hangover symptoms.This critical review comprehensively discussed those various food components including natural sources and several commercial plant-based products that may suppress the severity of alcohol hangover symptoms via their antioxidant and/or anti-inflammatory properties.This review also explored the proposed mechanism for how some of these food-based products might alleviate alcohol hangover symptoms.
As detailed, these natural compounds mainly reduced the levels of blood alcohol metabolites by increasing the activity of ADH and ALDH.The insights gained through this review may assist clinicians in understanding and managing alcohol-associated diseases.Given the current intense research activities in exploration of natural therapeutic prospects, we anticipate several breakthroughs in the development of natural medications to help drinkers with severe hangover symptoms.

F
I G U R E 2 Metabolism of ethanol into acetaldehyde by two enzymatic pathways.In the liver, alcohol dehydrogenase (ADH) plays a major role, while cytochrome P450 (CYP2E1) plays a minor role.the activation of pro-carcinogens by induction of CYP2E1.Ethanol can serve as a solvent to dissolve the carcinogens that are considered a contributing risk factor in promoting esophageal cancer and facilitating their penetration into the aerodigestive mucosa (Alzeer & Abou Hadeed, 2016; Husain et al., 2011).Acetaldehyde and other generated aldehydes during oxidative stress can crossreact to form hybrid adducts composed of different combinations of acetaldehyde-protein or acetaldehyde-DNA in the tissues.The clinical significance of this phenomenon is accelerated when alcohol is consumed with high levels of fat (which is susceptible to F I G U R E 3 Mitochondrial fatty acid beta-oxidation and its role in ethanol-induced fatty liver.Fatty acids enter into the cell.In the cytoplasm, fatty acids are converted to fatty Acyl-CoA by acyl-CoA synthase and then transferred to the mitochondrial matrix by VDAC, CPT I, CACT, and CPT II, step by step.Acyl-CoA then undergoes β-oxidation to produce acetyl-CoA for tricarboxylic acid cycle.These are the normal mechanisms for fatty acid catabolism.In the presence of alcohol, these mechanisms are impaired, resulting in morphologic changes in the liver cells and the accumulation of fats.ACS, Acyl-CoA synthase; CPT, carnitine O-palmitoyltransferase; CACT, carnitineacylcarnitine translocase; VDAC, voltage-dependent anion channel. of ALDH • Development of fatty acid β-oxidation • Increasing the activity of glutathione peroxidaseBailey et al. (2001),Cho et al. (2010),Videla & Guerri (2017) Herbal medicines (Camellia sinensis, Houttuynia cordata, Nelumbo nucifera G., Viscum album L., Lycium chinense L., Inonotus obliquus, Acanthopanax senticosus H., Glycyrrhiza uralensis, Pueraria thunbergiana, Liriope platyphylla, Polypori umbellati, Ixeris dentata, Acanthopanax sessiliflorus, Artemisia capillaris Thunb, Paeonia lactiflora Pallas, Plantago asiatica L., Malpighia glabra, Opuntia ficus indica, Ginkgo biloba, Salix alba, Zingiber officinale) • Activation of ADH and ALDH • Inhibition of pro-inflammatory mediators • Development of antioxidant activity Lee, Kim, et al. (2009), Lieb & Schmitt (2020), Noh et al. (2009), Yoon et al. (2011), You et al. (2016) Minerals • Acting as cofactor of antioxidant enzymes • Multivalent metals take part in oxidation-reduction reactions • Blocking the target receptors of ethanol in the brainMin et al. (2010), Ron & Wang (2009), Smith et al. (2009) Ginseng • Suppression of ethanol-induced oxidative stress by the antioxidant compounds Lee et al. (2014), Park et al. (2019), Sharma et al. (2020) Hovenia dulcis tree • Increasing the activity of ADH and ALDH • Development of antioxidant potential • Anti-nitration effect of flavonoid compounds in favor of improved metabolism of ethanol by catalase • Suppression of pro-inflammatory agents and increased level of anti-inflammatory compounds • Blocking the target receptors of ethanol Je et al. (2021), Kang et al. (2021), Kim et al. (2017), Wang et al. (2016) Fermented persimmon juice • Role of GABA in the increased activity of ADH and ALDH, decreasing the ethanol absorption, and suppression of oxidative stress Boby et al. (2021); Cha et al. (2011); Zhou et al. (2019); Zhu et al. (2019) Shiitake extract • Reducing the absorption of ethanol and acetaldehyde in the GI tract by slowing the peristaltic movement Uto-Kondo et al. (2020) An early in vivo trial report by Uto-Kondo et al. studied the detoxification and hepatoprotective effects of the extract form of shiitake, a popular edible mushroom in Japan and China, and its roles in reducing ethanol-induced metabolites.The authors found that shiitake extract, which contains a large amount of lentinic acid, could suppress the absorption of both ethanol and acetaldehyde from the stomach and jejunum, likely due to its property of slowing the peristaltic movements in the GI tract.Moreover, the administration of shiitake extract to rats was shown to decrease blood ethanol or acetaldehyde concentrations owing to a rise in the enzymatic activities of cytosolic ADH, cytosolic ALDH, and mitochondrial ALDH (ALDH2) in the stomach and liver (Uto-Kondo et al., 2020).The same authors also investigated the anti-hangover effects of garlic extract, which contains high concentrations of S-allyl-L-cysteine sulfoxide.The results suggested that garlic extract relieved intoxication and hangover by reducing intestinal alcohol and acetaldehyde absorption and metabolism.The garlic extract showed the most significant stimulatory effects on ALDH2 (Uto-Kondo et al., 2018).Srinivasan et al. studied the anti-hangover effectiveness and efficiency of several selected food commodities, including fruits, vegetables, cereals, pulses, dairy products, and spices, after alcohol consumption.The results showed that pear, sweet lime, and coconut water developed anti-hangover effects, which were validated by the evidence of increased ADH and ALDH activity in vitro.In contrast,