Scapa, one of my current Scottish whiskies

Scottish malt whisky, unlike other beverages such as red wine, tea or coffee, has received little attention with regards to its phenolic plant phytochemicals.

In the production of malt whisky the pure distilled spirit is aged in oak barrels for a number of years. During this aging constituents that make up the wood gradually dissolve into the spirit determining its flavour, colour and taste (Tanaka 2010). The wood of American white oak used to make many of the barrels used to age whisky contains significant amounts of an oak wood polyphenols called ellagitannins. The processing stages of making barrel for whisky production, including seasoning and toasting, results in various chemical changes in the ellagitannins of the wood resulting in the phenolic compounds in the whisky being rather different than the original oak wood polyphenols (Cadahia 2001). The original tannins decompose during toasting or charring of the barrels and then during the aging process oxygen molecules are absorbed through the wood further oxidising the dissolved phenolic compounds. The polyphenols in whisky are a mixture of products resulting from a complex chemical process (Tanaka 2010). These non-volatile components of whisky are known are whisky congeners, they are not found in the freshly distilled spirit but rather are a result of the long aging of good whisky. A range of these phenolic compounds were isolated from commercially bottled Japanese whisky including carboxyl ellagic acid, gallic acid, ellagic acid, brevifolin carboxylic acid, among others (Fujieda 2008). In another study ellagic acid, gallic acid, and lyoniresinol were found to be the principle polyphenols in a range of whiskies of both Japanese and Scottish origin. However, these three compounds only made up 20% of the antioxidant capacity of the whisky tested, suggesting there are a range of other polyphenols involved (Koga 2007).

Levels of gallic acid, ellagic acid, and lyoniresinol in whisky of different ages (Fujieda 2008).

Unlike other popular beverages whisky has been rather lacking in study regarding the potential effects of these plant phytochemicals when ingested by humans. One of the few studies on the subject, carried out at my own Rowett Institute, examined the concentration of phenolic compounds and antioxidant capacity of volunteers blood after drinking 100 millilitres, (3.5 ounces) of either red wine, a 12 y old malt whisky which had been matured in oak wood casks, or a `new make’ whisky which is the newly-distilled whisky spirit prior to maturation. Surely one of the more arduous nutrition studies ever carried out (Duthie et al. 1998).

Concentration of total phenols in volunteers blood after drinking whisky or red wine (Duthie 1998).

Both the whisky and red wine produced a similar rise in total phenols in the blood of volunteers, suggesting the phenolic compounds in whisky are rapidly absorbed after drinking. The ‘new make’ whisky did not cause any rise in blood phenols. Although the levels in the blood were similar between red wine and whisky, in fact proportionately more of the phenolic compounds were absorbed from the whisky than the wine. This may be due to the higher alcohol content enhancing their absorption, and different bioavailability of the compounds in wine and whisky. New made whisky did not result in any increase in phenols in the volunteers’ blood (Duthie et al. 1998).

Antioxidant capacity of volunteers blood after drinking whisky or red wine (Duthie 1998).

Drinking whisky or red wine increase the antioxidant capacity of the volunteers’ blood to a similar degree. Unexpectedly the ‘new make’ whisky caused a decrease in antioxidant capacity of the blood, possibly due to increased oxidative stress caused by the alcohol itself, or as suggested by the authors, the greater content of copper in the ‘new make’ whisky. This suggested that the phenolic compounds in whisky are absorbed and can influence the antioxidant capacity of the blood in a similar way to red wine, and that the aging process of whisky in oak barrels in key to these effects.

The phenolic compounds in whisky appear to be absorbed into the blood and a few small studies from Japan now hint at what effects these compounds may have in the body. Single malt whisky showed the ability to neutralise free radicals and there was a positive correlation between this activity and the how long the whisky had been aged (Koga 2007).  This antioxidant ability of whisky has been found to protect E. coli bacteria from oxidative damage caused by hydrogen peroxide, compared to the same amount of pure alcohol (Aoshima 2004). The specific compounds isolated from whisky have been shown to have a range of interesting effects. Isolated whisky phenolic compounds including ellagic acids suppressed allergic reactions to allergens in both isolated cells and in mice. These findings suggest that the phenolic compounds from whisky seemed to be beneficial to ameliorate allergic reactions (Itoh 2010). The isolated phenolic compounds from whisky were found to reduce the inflammation in isolated immune cells and in mice. These whisky phenolic compounds may be beneficial for the treatment of inflammatory disease (Itoh 2012). Ellagic acid prevented alcohol induced development of fatty liver in mice, although these were higher doses than found in whisky. These results provide a molecular basis for the prevention of alcohol-induced stress by the polyphenols in alcoholic beverages (Yao 2014). In human epithelial cells, the cells that line the blood vessels of the body, the activity of the enzyme heme oxygenase-1 was increased by the phenolic compounds isolated from whisky.  This effect only emerged in whisky aged in oak barrels. This heme oxygenase-1 enzyme is thought to protect the lining of the blood vessels from damage. Various epidemiological reports suggest a moderate consumption of alcoholic beverages appears to reduce some health risks in relation to human health. The, up-regulation of this enzyme in the cells lining the blood vessels by whisky might possibly contribute to the maintenance of blood vessel function (Suzuki 2010). These effects are interesting but should however be taken with some caution as the relevance of the potential effects, in the concentrations found in whisky, are unknown to human health.

The phenolic compound ellagic acid may have a direct effect in the gut ameliorating some of the harmful effects of alcohol on the lining of the gut. It has been shown that whisky is less irritating to the delicate lining of the gut, as compared with pure ethanol. This effect of whisky may be explained by ellagic acid, one of major polyphenols contained in whisky, and its radical scavenging action (Iino 2001). A later study confirmed that ellagic acid is able to directly protect the lining of the gut from damage and explains the less damaging effect of whisky on the stomach than pure alcohol (Iino 2002).  This is hardly to suggest that whisky is good for the gut, but at least its potential negative effects are mitigated by its polyphenols compared to pure alcohol.

The effect of whisky of uric acid levels in the blood has also been investigated. Alcohol generally increases the level of uric acid in the blood, both by increasing the production of uric acid in the liver and reducing how much is excreted in urine. This a concern for people with high blood uric acid levels who are at risk of gout, for which alcohol consumption is an important risk factor. However, unlike other alcoholic drinks, it has been found that whisky tended to lower the levels of uric acid in the blood (Nishioka 2002). This tendency was suggested to be partly due to the inhibition of xanthine oxidase, the enzyme that produces uric acid. The longer the whisky had been aged in oak casks the greater effect it had on reducing the activity of the xanthine oxidase enzyme. It was also found that whisky stimulated an increase in the amount of uric acid excreted in the urine by 27%. This improved excretion of uric acid seemed to be mainly responsible for the reduced uric acid after drinking whisky and showed that at a moderate level of drinking, whisky have different effects on uric acid than other types of alcohol (Nishioka 2002). More recently it has been suggested that the decreased serum urate level after whisky consumption may be mainly due to inhibition the uric acid transporters in the kidneys by the phenolic congeners in whisky. This would result in more uric acid being lost into the urine (Lu 2014). While this may make whisky a better choice than other drinks to those with  high blood uric acid levels or gout who wish to drink alcohol, caution should be applied, as the research on this subject is rather limited.

While these phenolic compounds may be appearing rather good now, there is a possible downside to their presence in whisky. Some older research (Damrau 1960), suggests that the same whisky congeners absorbed from the oat barrels can slow the metabolism of alcohol. This could explain the increased hangover symptoms reported by volunteers in the study, at least in comparison to vodka.

It is clear that aged malt whisky does contain phenolic compounds, originating from the oak wood barrels, and shaped by the long maturing of the whisky. These compounds, such as ellagic acid, do have the potential to beneficially affect the health of those imbibing of these spirits, above that pure alcohol would have on its own. These various phenols can potentially have a range of effects on our physiology, although it is still unclear how relevant these may be to our health. To quote one of the papers on this topic,

“We do not recommend drinking whiskey or wine as a method of antioxidant intake, since other beverages such as green tea and oolong tea also include many antioxidants such as catechin derivatives. However, you can think of the antioxidative activity of whiskey or wine if you often drink liquors. More epidemiological studies are also necessary to clarify whether the antioxidants in liquors are related favourably to human mortality.” – (Aoshima 2004)

It does maybe provide an excuse for the purchase of an older, longer matured, fine malt whisky. Perhaps be cautious with drinking to excess, as those very same compounds may increasing any resulting hangover.

 

Conflicts of interest: I do rather like good whisky.

References

Aoshima, H., Tsunoue, H., Koda, H. & Kiso, Y. 2004, “Aging of whiskey increases 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity“, Journal of Agricultural and Food Chemistry, vol. 52, no. 16, pp. 5240-5244.

“1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity of Japanese whiskey after various aging periods in oak barrels was measured to evaluate the antioxidative effects of whiskey. The activity of the whiskey increased with the aging period with high correlation. The activity of various types of whiskey was measured and shown to be correlated to the potentiation of the GABAA receptor response measured in a previous paper. However, the fragrant compounds in the whiskey which potentiated the GABAA receptor response had low DPPH radical scavenging activity, while phenol derivatives had high radical scavenging activity. The whiskey was extracted by pentane. The aqueous part showed the scavenging activity, whereas the pentane part did not. Thus, both the DPPH radical scavenging activity and the potentiation of the GABAA receptor response increased during whiskey aging in oak barrels, but were due to different components. The whiskey protected the H2O2-induced death of E. coli more than ethanol at the same concentration as that of the whiskey. The changes that occurred in the whiskey during aging may be the reason aged whiskies are so highly valued.“

Cadahia, E., Varea, S., Munoz, L., de Simon, B. & Garcia-Vallejo, M. 2001, “Evolution of ellagitannins in Spanish, French, and American oak woods during natural seasoning and toasting“, Journal of Agricultural and Food Chemistry, vol. 49, no. 8, pp. 3677-3684.

“The evolution of tannins in Spanish oak heartwood of Quercus robur L., Quercus petraea Liebl.,Quercus pyrenaica Wild., and Quercus faginea Lam. was studied in relation to the processing of wood in barrel cooperage. Their evolution was compared with that of French oak of Q. robur (Limousin, France) and Q. petraea (Allier, France) and American oak of Quercus alba L. (Missouri), which are habitually used in cooperage. Two stages of process were researched: the seasoning of woods during 3 years in natural conditions and toasting. Total phenol and total ellagitannin contents and optical density at 420 nm of wood extracts were determined. The ellagitannins roburins A-E, grandinin, vescalagin, and castalagin were identified and quantified by HPLC, and the molecular weight distribution of ellagitannins was calculated by GPC. During the seasoning process the different ellagitannin concentrations decreased according to the duration of this process and in the same way as those in French and American woods. The toasting process also had an important influence on the ellagitannin composition of wood. Roburins A-E, grandinin, vescalagin, and castalagin decreased during this process in the Spanish wood species, in the same proportion as in the French and American ones. Also, the seasoning and toasting processes lead to qualitative variations in the structure of ellagitannins, especially in the molecular weight distribution, as was evidenced by GPC analysis of their acetylated derivatives.”

Damrau, F.,Liddy, E. 1960, “Hangovers and Whisky Congeners: Comparison of Whisky with Vodka“, Journal of the National Medical Association, vol. 52, no. 4, pp. 262–265.

“IN a field survey’ of moderate social drinkers, many of the persons interviewed reported less hangover with vodka as compared with the same amount of whisky. Further studies established an important role of the whisky congeners in causing hangover.2 Investigation of the toxicology of whisky congeners2 demonstrated that, even in as small amount as 2 ounces of whisky, the congeners increase and prolong the action of alcohol and often produce definite after-effects lasting into the following day. These after-effects were absent or minimal when the same amount of alcohol was consumed in the form of vodka.* The present report deals with mild hangovers occurring in unaccustomed or social drinkers. In this study the term “hangover” is used according to its general definition :3 namely, “headache, nausea, etc. occurring as an after-effect of drinking much alcoholic liquor.” More specifically, we have concentrated our attention on the after-effects of small quantities of whisky and vodka, respectively, so as to eliminate the overshadowing effects of large excesses of alcohol. In this way we have been able to demonstrate a definite difference between whisky and vodka with reference to the occurrence of mild hangovers in unaccustomed and social drinkers. The results can be attributed to the great difference in their congeneric content as shown in Table 1.”

Duthie, G., Pedersen, M., Gardner, P., Morrice, P., Jenkinson, A., McPhail, D. & Steele, G. 1998, “The effect of whisky and wine consumption on total phenol content and antioxidant capacity of plasma from healthy volunteers“, European Journal of Clinical Nutrition, vol. 52, no. 10, pp. 733-736.

“OBJECTIVE: To assess whether consumption of 100 ml of whisky or red wine by healthy male subjects increased plasma total phenol content and antioxidant capacity.

DESIGN: A Latin square arrangement to eliminate ordering effects whereby, after an overnight fast, nine volunteers consumed 100 ml of red wine, malt whisky or unmatured ‘new make’ spirit. Each volunteer participated on three occasions one week apart, consuming one of the beverages each time. Blood samples were obtained from the anticubital vein at intervals up to 4h after consumption of the beverages when a urine sample was also obtained.

RESULTS: Within 30 min of consumption of the wine and whisky, there was a similar and significant increase in plasma total phenol content and antioxidant capacity as determined by the ferric reducing capacity of plasma (FRAP). No changes were observed following consumption of ‘new make’ spirit.

CONCLUSIONS: Consumption of phenolic-containing alcoholic beverages transiently raises total phenol concentration and enhances the antioxidant capacity of plasma. This is compatible with suggestions that moderate alcohol usage and increased antioxidant intake decrease the risk of coronary heart disease.”

Fujieda, M., Tanaka, T., Suwa, Y., Koshimizu, S. & Kouno, I. 2008, “Isolation and structure of whiskey polyphenols produced by oxidation of oak wood ellagitannins“, Journal of Agricultural and Food Chemistry, vol. 56, no. 16, pp. 7305-7310.

“Three new phenolic compounds named whiskey tannins A and B and carboxyl ellagic acid were isolated from commercial Japanese whiskey, along with gallic acid, ellagic acid, brevifolin carboxylic acid, three galloyl glucoses, a galloyl ester of phenolic glucoside, 2,3-(S)-hexahydroxydiphenoylglucose, and castacrenin B. Whiskey tannins A and B were oxidation products of a major oak wood ellagitannin, castalagin, in which the pyrogallol ring at the glucose C-1 position of castalagin was oxidized to a cyclopentenone moiety. These tannins originated from ellagitannins contained in the oak wood used for barrel production; however, the original oak wood ellagitannins were not detected in the whiskey. To examine whether the whiskey tannins were produced during the charring process of barrel production, pyrolysis products of castalagin were investigated. Dehydrocastalagin and a new phenolcarboxylic acid trislactone having an isocoumarin structure were isolated, along with castacrenin F and ellagic acid. However, whiskey tannins were not detected in the products.”

Iino, T., Nakahara, K., Miki, W., Kiso, Y., Ogawa, Y., Kato, S. & Takeuchi, K. 2001, “Less damaging effect of whisky in rat stomachs in comparison with pure ethanol – Role of ellagic acid, the nonalcoholic component“, Digestion, vol. 64, no. 4, pp. 214-221.

“BACKGROUND/AIM: Ellagic acid (EA), one of the polyphenols that are abundantly contained in whisky as a nonalcoholic component, has antioxidant and anti-inflammatory activities. In the present study, we compared the action of whisky and pure ethanol on the rat gastric mucosa, and examined the role of EA in the less-damaging effect of whisky in the stomach.

METHODS: Under urethane anesthesia, a rat stomach was mounted in an ex vivo chamber, perfused with saline, and the transmucosal potential difference (PD) was measured before and after exposure to whisky (Yamazaki, Suntory) and ethanol (43%). In a separate study, the animals were given whisky or ethanol (1 ml, 43%) p.o. under unanesthetized conditions, killed 1 h later, and the gastric mucosa was examined for hemorrhagic lesions.

RESULTS: Both whisky and ethanol caused a PD reduction, resulting in damage in the stomach, but these responses were less marked in the case of whisky. Although the reduced PD recovered gradually after removal of ethanol, this process was significantly expedited by co-application of EA (80 microg/ml), the recovery rate being much the same as that observed after exposure to whisky. The less-damaging effect of whisky was confirmed in unanesthetized rats after p.o. administration of these agents. In addition, EA (1-30 mg/kg), administered p.o. together with absolute ethanol (99.9%), reduced the severity of gastric lesions induced by ethanol, in a dose-dependent manner, and the effect at 30 mg/kg was equivalent to that obtained by the whisky component containing several low- and high-molecular-weight polyphenols. EA had a scavenging action against both oxygen and hydroxyl radicals in vitro, the effect being equivalent to that of catechol or alpha-tocopherol.

CONCLUSION: These results suggest that whisky is less irritating to the gastric mucosa, as compared with pure ethanol, and this property of whisky may be explained by EA, one of polyphenols contained in whisky, and its radical scavenging action.“

Iino, T., Tashima, K., Umeda, M., Ogawa, Y., Takeeda, M., Takata, K. & Takeuchi, K. 2002, “Effect of ellagic acid on gastric damage induced in ischemic rat stomachs following ammonia or reperfusion“, Life Sciences, vol. 70, no. 10, pp. 1139-1150.

“We examined the effect of ellagic acid (EA), one of the polyphenols that are abundantly contained in whisky as a nonalcoholic component, on gastric lesions induced by ammonia plus ischemia or ischemia/reperfusion in rats, in relation to the antioxidative system. Under urethane anesthesia, a rat stomach was mounted in an ex vivo chamber, and the following two experiments were performed; 1) a stomach was made ischemic (1.5 ml/100 g body weight) for 20 min, followed by reperfusion for 15 min in the presence of 100 mM HCl; 2) a stomach was made ischemic by bleeding from the carotid artery (1 ml/100 g body weight), followed by intragastric application of ammonia (NH4OH: 120 mM). EA (0.1-10 mg/ml) was applied in the chamber 30 min before the onset of ischemia. Gastric potential difference (PD) and mucosal blood flow (GMBF) were measured before, during and after 20 min of ischemia. Ischemia/reperfusion caused a profound drop in GMBF followed by a return, and resulted in hemorrhagic lesions in the stomach in the presence of 100 mM HCI. These lesions were dose-dependently prevented by EA with suppression of lipid peroxidation but no effect on GMBF, and the effect at 6 mg/ml was almost equivalent to that of superoxide dismutase (SOD: 15000 unit/kg/hr) infused i.v. during a test-period. On the other hand, application of NH4OH to the ischemic stomach produced a marked reduction in PD, resulting in severe hemorrhagic lesions. These changes were prevented with both EA and SOD. In addition, EA had a potent scavenging action against monochloramine in vitro. These results suggest that EA exhibits gastric protective action against gastric lesions induced by NH4OH or reperfusion in the ischemic stomach, probably due to its anti-oxidative activity. This property of EA partly explains the less damaging effect of whisky in the stomach and may be useful as the prophylactic for Helicobacter pylori-associated gastritis.“

Itoh, T., Ando, M., Tsukamasa, Y., Wakimoto, T. & Nukaya, H. 2012, “Whiskey Congeners Suppress LPS/IFN gamma-Induced NO Production in Murine Macrophage RAW 264 Cells by Inducing Heme Oxygenase-1 Expression“, Journal of Agricultural and Food Chemistry, vol. 60, no. 51, pp. 12491-12500.

Whiskey includes many nonvolatile substances (whiskey congeners; Whc) that seep from the oak cask during the maturation process. To date, many functions of Whc have reported, such as antiallergy and antimelanogenesis. This study examined the effect of Whc on LPS/IFNγ-induced nitric oxide (NO) production in murine macrophage RAW 264 cells. Whc suppressed LPS/IFNγ-induced NO production in a concentration-dependent manner. To determine the active compounds in Whc, the effect of 10 major compounds isolated from Whc on LPS/IFNγ-induced NO production was examined. Coniferylaldehyde (CA) and sinapylaldehyde (SiA) strongly suppressed LPS/IFNγ-induced NO production. Pretreatment with Whc, CA, and SiA induced heme oxygenase-1 (HO-1) expression. The expression of HO-1 by Whc, CA, and SiA pretreatment was due to activation of Nrf2/ARE signaling via the elevation of intracellular reactive oxygen species. To investigate the in vivo effects of Whc, Whc was administered to mice with antitype II collagen antibody-induced arthritis, and we the arthritis score and hind paw volume were measured. Administration of Whc remarkably suppressed the arthritis score and hind paw volume. Taken together, these findings suggest that Whc is beneficial for the treatment of inflammatory disease.

Itoh, T., Tsukane, M., Koike, M., Nakamura, C., Ohguchi, K., Ito, M., Akao, Y., Koshimizu, S., Nozawa, Y., Wakimoto, T., Nukaya, H. & Suwa, Y. 2010, “Inhibitory Effects of Whisky Congeners on IgE-Mediated Degranulation in Rat Basophilic Leukemia RBL-2H3 Cells and Passive Cutaneous Anaphylaxis Reaction in Mice“, Journal of Agricultural and Food Chemistry, vol. 58, no. 12, pp. 7149-7157.

“Whisky is matured in oak casks. Many nonvolatile substances (whisky congeners, WC) seep from the oak cask during the maturing process. In this study, three antiallergic agents (syringaldehyde, SA; lyoniresinol, Lyo; and ellagic acid, EA) were isolated from WC. Treatment with SA, Lyo, and EA reduced the elevation of intracellular free Ca(2+) concentration ([Ca(2+)]i) and intracellular ROS production caused by FcepsilonRI activation. The inhibitions of the elevation of [Ca(2+)]i and intracellular ROS production by SA and Lyo were mainly due to the suppression of the NADPH oxidase activity and scavenging of the produced radical, respectively. On the other hand, EA inactivated spleen tyrosine kinase and led to the inhibition of the elevation of [Ca(2+)]i and intracellular ROS production. Furthermore, it was found that WC strongly inhibited IgE binding to the FcepsilonRIalpha chain, whereas SA, Lyo, and EA did not indicate this inhibitory effect. These results suggest that WC inhibits allergic reactions through multiple mechanisms. To disclose the in vivo effects of WC, SA, Lyo, and EA, these compounds were administered to type I allergic model mice, and the passive cutaneous anaphylaxis (PCA) reaction was measured. These compounds remarkably suppressed the PCA reaction. Taken together, these findings suggest that WC seemed to be beneficial to ameliorate allergic reactions.“

Koga, K., Taguchi, A., Koshimizu, S., Suwa, Y., Yamada, Y., Shirasaka, N. & Yoshizumi, H. 2007, “Reactive oxygen scavenging activity of matured whiskey and its active polyphenols“, Journal of Food Science, vol. 72, no. 3, pp. S212-S217.

“The quality of whiskey is known to improve remarkably by its storage over many years. This process is commonly termed “maturing.” In this process, polyphenols derived from lignin and tannin of the barrel have an important role in not only forming the matured flavor and taste but also contributing to the advance of clustering ethanol and water in whiskey. It is also likely that polyphenols generally possess reactive oxygen (RO) scavenging activity. The present study evaluated the RO scavenging activity (free-radical scavenging activity, H(2)O(2) reduction activity under peroxidase coculture, and H(2)O(2)scavenging activity) of 24 single malt whiskeys with a maturation age of 10 to 30 y produced in Japanese, Scotch (Islay), or Scotch (Speyside and Highland) regions. Single malt whiskey not only showed RO scavenging activity but there was also a positive correlation between this activity and the maturation age of whiskey exceeding the difference resulting from the manufacturing region. A nonvolatile fraction derived from the barrel was responsible for RO scavenging activity. In particular, the contents of ellagic and gallic acids and lyoniresinol, the main polyphenolic compounds in whiskey, increased with maturation age. For the free-radical scavenging activity per molecule, each compound was 1.68 to 3.14 times that of trolox (a water-soluble vitamin E). The activities of ellagic acid, gallic acid, and lyoniresinol in the whiskey (Yamazaki 18) were equivalent to that of 80.3, 31.2, and 11.1 ppm trolox, respectively. Accordingly, the total activity of these 3 compounds accounted for about 20% of the activity of the whiskey (630.7 ppm trolox).”

Lu, Y., Nakanishi, T., Fukazawa, M. & Tamai, I. 2014, “How Does Whisky Lower Serum Urate Level?”, Phytotherapy Research, vol. 28, no. 5, pp. 788-790.

“Clinical studies have shown that moderate whisky consumption increased renal excretion of urate into urine and decreased serum urate level, but the mechanism involved has not been established. Because renal reabsorption influences serum urate level, the effects of the whisky congeners on urate transporters, urate transporter 1 (URAT1), and voltage-driven urate transporter (URATv1) involved in reabsorptive transport of urate were examined. In transporter-expressing Xenopus oocytes, 12-year-old and 18-year-old whisky congeners inhibited urate uptake by URAT1 with IC50 values of 0.08 ± 0.01 and 0.04 ± 0.01 mg/mL, respectively, while urate uptake by URATv1 was inhibited only at 1 mg/mL. Decreased serum urate level after whisky consumption may be mainly due to inhibition of URAT1 by the congeners.“

Nishioka, K., Sumida, T., Iwatani, M., Kusumoto, A., Ishikura, Y., Hatanaka, H., Yomo, H., Kohda, H., Ashikari, T., Shibano, Y. & Suwa, Y. 2002, “Influence of moderate drinking on purine and carbohydrate metabolism“, Alcoholism-Clinical and Experimental Research, vol. 26, no. 8, pp. 20S-25S.

BACKGROUND: We examined the influences of a moderate intake level of three types of alcoholic beverages–beer, whisky, and Shochu (Japanese distilled liquor)–on purine and carbohydrate metabolism and excretion in healthy male volunteers, concerning (1) the extent of contribution of purine bodies contained in beer to uric acid metabolism and (2) a comparison between two types of distilled spirits with (whisky) and without (Shochu) aging in oak wood barrel storage.

METHODS: Three sets of studies were conducted in which 10 to 13 healthy adult men were instructed to drink three types of alcoholic beverages at a slightly higher level (0.8 ml of ethanol equivalent/kg body weight) than moderate drinking (approximately 30.4 ml or less for men). A low purine beer was test-manufactured by treating nucleosides that were contained in wort and remained in beer with purine nucleoside phosphorylase derived from Ochrobacterium anthropi, thereby converting them into corresponding purine bases that were easily assimilated by beer yeast.

RESULTS: Although beer intake enhanced the level of serum uric acid by 13.6%, blood glucose by 26.7%, and insulin level by 5.1-fold, drinking a moderate level of distilled liquor (whisky, Shochu) did not increase the serum uric acid level or the other two parameters. The serum uric acid level observed after drinking beer with a purine body concentration reduced by 28% (68% in nucleosides and purine bases) was almost identical to the level observed after drinking regular beer. Whisky has been found to have a property that decreases the serum uric acid level. Excretion of uric acid from blood is increased by 27% after drinking whisky.

CONCLUSIONS: Moderate drinking of distilled liquors did not enhance serum uric acid level, blood glucose, or insulin level in healthy male subjects. Increased serum uric acid after beer intake could not be explained mostly with their purine body congeners. Whisky showed the eliminative property in serum uric acid through excretion of it from blood to urine. At a moderate drinking level, beer and whisky have different effects on purine metabolism or excretion.”

Suzuki, K., Nemoto, A., Tanaka, I., Koshimizu, S., Suwa, Y. & Ishihara, H. 2010, “Induction of Heme Oxygenase-1 by Whisky Congeners in Human Endothelial Cells“, Journal of Food Science, vol. 75, no. 6, pp. H163-H166.

“It is expected that the production of the cytoprotective heme oxygenase-1 (HO-1) protein in endothelial cells would reduce severity of vascular injuries, while phenolic compounds are known to induce HO-1 mRNA and protein in various cells. We investigated the activation of HO-1 by whisky, which contains various phenolic substances. The congeners of whisky stored from 4 to 18 y in oak barrels were shown to induce an increase of HO-1 protein in human umbilical vein endothelial cells, while those of freshly distilled whisky spirit exhibited no activity. To determine the compounds with potent HO-1-inducing activity among the whisky congeners, several chemicals that had been reported to exist in whisky or oak barrels were screened, and coniferyl aldehyde and sinapyl aldehyde showed the activity. Thus, compounds that emerged in whisky during barrel storage induced cytoprotective protein, HO-1, in human endothelial cells.”

Tanaka, T., Matsuo, Y. & Kouno, I. 2010, “Chemistry of Secondary Polyphenols Produced during Processing of Tea and Selected Foods“, International Journal of Molecular Sciences, vol. 11, no. 1, pp. 14-40.

“This review will discuss recent progress in the chemistry of secondary polyphenols produced during food processing. The production mechanism of the secondary polyphenols in black tea, whisky, cinnamon, and persimmon fruits will be introduced. In the process of black tea production, tea leaf catechins are enzymatically oxidized to yield a complex mixture of oxidation products, including theaflavins and thearubigins. Despite the importance of the beverage, most of the chemical constituents have not yet been confirmed due to the complexity of the mixture. However, the reaction mechanisms at the initial stages of catechin oxidation are explained by simple quinone–phenol coupling reactions. In vitro model experiments indicated the presence of interesting regio- and stereoselective reactions. Recent results on the reaction mechanisms will be introduced. During the aging of whisky in oak wood barrels, ellagitannins originating from oak wood are oxidized and react with ethanol to give characteristic secondary ellagitannins. The major part of the cinnamon procyanidins is polymerized by copolymerization with cinnamaldehyde. In addition, anthocyanidin structural units are generated in the polymer molecules by oxidation which accounts for the reddish coloration of the cinnamon extract. This reaction is related to the insolubilization of proanthocyanidins in persimmon fruits by condensation with acetaldehyde. In addition to oxidation, the reaction of polyphenols with aldehydes may be important in food processing.”

Yao, R., Yasuoka, A., Kamei, A., Ushiama, S., Kitagawa, Y., Rogi, T., Shibata, H., Abe, K. & Misaka, T. 2014, “Nuclear Receptor-Mediated Alleviation of Alcoholic Fatty Liver by Polyphenols Contained in Alcoholic Beverages“, Plos One, vol. 9, no. 2, pp. e87142.

“To elucidate the effect of the polyphenols contained in alcoholic beverages on the metabolic stress induced by ethanol consumption, four groups of mice were fed for five weeks on Lieber’s diet with or without ethanol, with ethanol plus ellagic acid, and with ethanol plus trans-resveratrol. Alcoholic fatty liver was observed in the group fed the ethanol diet but not in those fed the ethanol plus polyphenol diets. Liver transcriptome analysis revealed that the addition of the polyphenols suppressed the expression of the genes related to cell stress that were up-regulated by ethanol alone. Conversely, the polyphenols up-regulated the genes involved in bile acid synthesis, unsaturated fatty acid elongation, and tetrahydrofolate synthesis that were down-regulated by ethanol alone. Because parts of these genes were known to be regulated by the constitutive androstane receptor (CAR), we performed the same experiment in the CAR-deficient mice. As a result, fatty liver was observed not only in the ethanol group but also with the ethanol plus polyphenol groups. In addition, there was no segregation of the gene expression profiles among these groups. These results provide a molecular basis for the prevention of alcohol-induced stress by the polyphenols in alcoholic beverages.”