Pueraria lobata (Kudzu root) hangover remedies and acetaldehyde-associated neoplasm risk

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Pueraria lobata (Kudzu root) hangover remediesand acetaldehyde-associated neoplasm risk

Neil R. McGregor*University of Melbourne, Faculty of Medicine, Dentistry and Health Sciences, 9 Auburn Grove, Armadale, Victoria 3143, Australia

Received 22 October 2006; received in revised form 2 May 2007; accepted 28 July 2007

Abstract

Recent introduction of several commercial Kudzu root (Pueraria lobata) containing hangover remedies has occurred in western coun-tries. The available data is reviewed to assess if there are any potential concerns in relationship to the development of neoplasm if theseproducts are used chronically. The herb Pueraria has two components that are used as traditional therapies; Pueraria lobata, the root basedherb and Pueraria flos, the flower based herb. Both of these herbal components have different traditional claims and constituents. Puerariaflos, which enhances acetaldehyde removal, is the traditional hangover remedy. Conversely, Pueraria lobata is a known inhibitor of mito-chondrial aldehyde dehydrogenase (ALDH2) and increases acetaldehyde. Pueraria lobata is being investigated for use as an aversion ther-apy for alcoholics due to these characteristics. Pueraria lobata is not a traditional hangover therapy yet has been accepted as the registeredactive component in many of these hangover products. The risk of development of acetaldehyde pathology, including neoplasms, is asso-ciated with genetic polymorphism with enhanced alcohol dehydrogenase (ADH) or reduced ALDH activity leading to increased acetalde-hyde levels in the tissues. The chronic usage of Pueraria lobata at times of high ethanol consumption, such as in hangover remedies, maypredispose subjects to an increased risk of acetaldehyde-related neoplasm and pathology. The guidelines for Disulfiram, an ALDH2 inhib-itor, provide a set of guidelines for use with the herb Pueraria lobata. Pueraria lobata appears to be an inappropriate herb for use in herbalhangover remedies as it is an inhibitor of ALDH2. The recommendations for its use should be similar to those for the ALDH2 inhibitor,Disulfiram. � 2007 Elsevier Inc. All rights reserved.

Keywords: Alcohol drinking; Pueraria lobata; Acetaldehyde; Aldehyde dehydrogenase; Alcohol dehydrogenase; Head and neck neoplasms

Alcohol dehydrogenase (ADH) (EC.1.1.1.1) and alde-hyde dehydrogenase (ALDH) (EC.1.2.1.3) are the two en-zymes that metabolize alcohol and the pathway is shownin Fig. 1. Both of these enzymes are classified as phase 1xenobiotic metabolizing enzymes, and this pathway is im-portant for the degradation of a number of drugs, dietarysubstances, and other environmental agents (Sladek,2003). Therefore, this metabolic pathway has other impor-tant roles in metabolism apart from the degradation of alco-hol. Disturbance of the activities of these enzymes andaccumulation of the intermediate, acetaldehyde, in the caseof ethanol, is likely to have significant consequences to thehost. Also of significance is the high level of metabolism ofalcohol after acute intoxication may alter the ability of thebody to deal with other xenobiotic substances and may leadto the development of pathology, if these exposures occurchronically.

Acetaldehyde is a toxic substance and increases are as-sociated with (1) the development of acute alcohol with-drawal symptoms or ‘‘hangover’’ after acute intoxication(Eriksson, 2001); and with chronic exposure; (2) the devel-opment of acetaldehyde-related pathology such as pancrea-titis and cirrhosis (Chao et al., 2003); and (3) an increasedrisk for the development of acetaldehyde-related neoplasm(Brooks and Theruvathu, 2005; Burton, 2005; O’Hanlon,2005; Poschl and Seitz, 2004; Purohit et al., 2005; Visapaaet al., 2004). In the case of alcohol metabolism, any envi-ronmental or genetic factor that disturbs this metabolic pro-cess may alter the degree of hangover and or the risk ofdevelopment of acetaldehyde-related neoplasm, liver andpancreatic disease.

Recently, a group of commercially available productshave appeared in Western societies which are promoted foruse with acute alcohol withdrawal or hangover and these con-tain a herb that inhibits the mitochondrial ALDH (ALDH2)(Keung and Vallee, 1993). The use of this herb, Pueraria lo-bata or Kudzu, in such a product appears contradictory to the

* Tel.: þ61-395-096939; fax: þ61-395-009494.

E-mail address: [email protected] (N.R. McGregor)

0741-8329/07/$ e see front matter � 2007 Elsevier Inc. All rights reserved.

doi: 10.1016/j.alcohol.2007.07.009

Alcohol 41 (2007) 469e478


traditional claims and may influence not only hangoversymptom expression but also risk of acetaldehyde-relateddisease and neoplasms (Bensky et al., 2004).

A review of the literature is undertaken to evaluate thepotential effects of ingestion of Pueraria lobata at the sametime as ingestion of alcohol and/or smoking and the rela-tionships with potential development of acetaldehyde-related neoplasm.

Genetic polymorphic anomalies in the alcohol metaboliz-ing enzymes have been noted to result in accumulation of ac-etaldehyde and represent a significant disturbance in thisxenobiotic removal system and do have pathologic potential.To understand the potential outcomes, in relationship to alco-hol, we need to review the metabolic processes involved,including the genetic and environmental aspects.

Human ALDH isoenzymes and acetaldehyde

Humans have 17 families of ALDH enzymes and theseare reviewed in detail in several papers (Agarwal, 2001;Sladek, 2003). For the purposes of this review, we will re-strict our discussion to the first three families of ALDHs asthese are the major ethanol metabolismeassociated en-zymes in humans. Family one is located in the cytoplasmand termed ALDH1. Family two are the mitochondrialenzymes, ALDH2, and family three are the inducibleenzymes and respond to increased xenobiotic challenge(ALDH3) (Agarwal, 2001; Sladek, 2003). Each of these en-zymes is a homotetramer of the various isoenzymes. In hu-mans, ALDH2 is the most prominent enzyme involved inalcohol-associated acetaldehyde oxidation (Klyosov et al.,1996).

Polymorphism has been noted in all three families withthree variants in each of ALDH1 and ALDH2 and seven inALDH3. The ALDH2*2 variant, which is found in 50% ofAsian populations and 40% of South American Indians, hastotal loss of activity and is the result of a single nucleotideglutamic acid to lysine substitution at the 14th positionfrom the carboxyl terminal (Hempel et al, 1984; Yoshidaet al., 1985). The heterozygote ALDH2*1/2*2 subjectshave a reduced removal rate of acetaldehyde compared withthe normal ALDH2*1 individuals and have higher acetalde-hyde levels. Variants in ALDH3 have also been reportedand these are higher in European populations (Agarwal,2001). The outcome of these ALDH variants is that the re-moval rate of acetaldehyde is reduced resulting in increasedacetaldehyde levels. When this system is deregulated, alco-hol is metabolized through alternative metabolic systemssuch as cytochrome p-450 (Cytochrome p-450 [number

2E1] or Microsomal Ethanol Oxidizing System), the fattyacid ethyl ester synthase system and catalase (Agarwal,2001).

The tissue distribution of the ALDH is quite variable:ALDH1 is highest in kidney, stomach mucosa, and salivaryglands; ALDH2 is highest in liver, kidney, and eye lens;whereas ALDH3 is highest in stomach mucosa, cornea,breast, lung, oesophagus, and pancreas (Sladek, 2003). Al-though each of the various ALDHs show alteration in tissuedistribution, there are also differences in the ADH:ALDH ra-tios within tissues which may be a significant reason for thedifferent susceptibilities of those tissues to develop acetalde-hyde-related pathology. Table 1 shows the relative variationof ADH and ALDH and the ADH:ALDH ratios within thevarious upper gastrointestinal tract sites (Dong et al., 1996;Yin et al., 1993). The oesophagus would potentially havethe highest concentrations of acetaldehyde after ethanol in-gestion as it metabolizes the conversion of ethanol to acetal-dehyde at a more rapid rate than it removes acetaldehyde.This pattern of ADH:ALDH, with a lack of ALDH2, appearsto be consistent with that of skin (Cheung et al., 1999). ThisADH:ALDH ratio variation is well demonstrated whencomparing stomach and oesophagus, where the oesophagealepithelium has a four-fold higher induction of ADHcompared with the stomach, yet has an 80% reduction inALDH expression compared with the stomach with the sameethanol and acetaldehyde stimuli (Yin et al., 1993). Thus, tis-sue variation in the induction of ADH and ALDH may havea significant bearing on the susceptibility of various tissues todevelop acetaldehyde-related pathology.

ALDH, acetaldehyde, and pathology

A mechanistic outline has been proposed in Fig. 2 for al-cohol increased acetaldehyde and its related potential pathol-ogy (Frank et al., 1984; Homann et al., 1997). Carriage of theinactive ALDH2*2 results in higher tissue acetaldehydelevels. Microbial action has been linked to increased alco-hol-related production of acetaldehyde in both the upper

Table 1

Relative activities of ADH and ALDH and the ratio of ADH and ALDH in

relationship to the upper gastrointestinal tract tissue distribution (from

Dong et al., 1996 and Yin et al., 1993)

Tissue Total ADH Total ALDH ADH:ALDH ratio

Gingiva 1 1 1.0

Tongue 0.4 0.3 1.3

Esophagus 5.4 2.2 2.5

Stomach 1.6 5.6 0.3

ADH 5 Alcohol dehydrogenase; ALDH 5 Alcohol dehydrogenase.

Note: The higher the ADH:ALDH ratio the higher the likelihood for

the tissue to have elevated acetaldehyde when drinking alcohol or elevated

xenobiotic-aldehyde intermediates if xenobiotics are being metabolized

through this enzyme system.

The enzyme units for ADH and ALDH are expressed as the nmol/min/

g tissue. The gingival tissue activity was used as the relative activity to

which the other tissues are compared.

Acetaldehyde

CH3CHO

Ethanol Acetate

CH3CH

2OH CH

3CHOOH

ADH ALDH

Fig. 1. The metabolic pathway for alcohol. ADH, Alcohol dehydroge-

nase; ALDH, Aldehyde dehydrogenase.

470 N.R. McGregor / Alcohol 41 (2007) 469e478


gastrointestinal tract (Homann et al., 2001) and the bowel(Homann et al., 2000a, 2000b). Several compounds areknown to inhibit ALDH and lead to increased acetaldehydelevels (Hart and Faiman, 1995). Rapid metabolizing formsof ADH and inhibited ALDH will also result in higher acet-aldehyde levels. In a similar mode, the tissue differences inADH:ALDH ratios also are an important aspect of the selec-tive tissue damage associated with the development of acet-aldehyde-related pathology (see Table 1). Smoking is knownto increase salivary acetaldehyde and this appears to occursynergistically with both the alcohol-related and microbial-related increases in acetaldehyde (Homann et al., 2000a,2000b). Thus, the development of increased acetaldehydemay result from multiple different mechanisms and occurat different levels within various tissues.

Homozygote ALDH2*2 subjects rarely drink and haveaversion to drinking due to the severity of acute alcohol in-toxicationeinduced symptoms associated with increased ac-etaldehyde levels. However some heterozygote ALDH2*1/2*2 subjects do drink, although this is at lower rates thanALDH2*1 subjects (see Fig. 3) (Yokoyama et al., 2003). Inrecent years, there has been an increase in drinking withinthe Japanese population; in 1979, 2.5% of alcoholics wereheterozygote for ALDH2, in 1986, it was 8.0%, and in1992, it was 13.0% (Higuchi et al., 1996). Analysis of the rea-sons for this increase in alcoholic ALDH2 heterozygote Jap-anese men was not found to be based upon the same alcoholdependence/abuse characteristics seen in the homozygoteALDH2*1 subjects (Takeshita et al., 1998). TheALDH2*2/2*2 homozygote, if they were drinkers, drinklarger quantities of alcohol and did so habitually (Okamotoet al., 2001). This drinking behavior displayed by theALDH2*2 subjects may be the same as seen in Caucasian

subjects, where continual drinking is apparently used to re-lieve symptoms (Earleywine, 1993a, 1993b; Span and Ear-leywine, 1999) or alternatively, the drinking may be relatedto the development of euphoria. This drinking-related eupho-ria has been documented in some individuals taking theALDH inhibitor, Disulfiram (Brown et al., 1983). Increasedacetaldehyde exposure due to increased drinking mayincrease the risk of development of acetaldehyde-relatedpathology (Brennan et al., 2004). Thus, the carriage ofALDH2*2 or inhibitors of ALDH2 are associated with in-creased drinking in up to 13% of carrier subjects and thismay be related to increased euphoria or the need to reducealcohol intoxication hangover symptoms.

ALDH, acetaldehyde, and neoplasm

Asian subjects who are homozygote for ALDH2*2 havea reduced rate of neoplasm and the majority have an aver-sion to drinking alcohol (Eriksson, 2001; Yokoyama et al.,2005a). However, the homozygote ALDH2*2 subjects, whodo drink, drink to a greater level than those who are homo-zygote for ALDH2*1 (Okamoto et al., 2001) and have adramatic increase in risk for the development of acetalde-hyde-related neoplasm (Yokoyama et al., 1996b). Subjectswith ALDH2*1/2*2 also have an increased risk of develop-ing acetaldehyde-related neoplasm (Hori et al., 1997;Yokoyama et al., 1996a, 1998, 1996c). Table 2 shows theodds ratios for oesophageal neoplasm in alcoholic subjectsrelated to their drinking levels and their ALDH2 gene al-leles (Yang et al., 2005). One study suggests that high alco-hol consumption and the ALDH2*2 gene are also related toan increase in rectal neoplasm (Matsuo et al., 2002). Thus,

ALDH2*2 Alleles ALDH Alleles

Acetaldehyde Oxidation

Alcohol Oxidation

AHD2*2 & ADH3*1 Alleles

ALDH inhibitors

Acetaldehyde

Microbial Activity

Tissue ADH:ALDH ratio

Pathology

Smoking

Fig. 2. Mechanistic pathways for increasing acetaldehyde and risk of neoplasm in relationship to ethanol metabolism. The presence of alcohol dehydroge-

nase 2*2 (ALDH2*2), which is inactive, and inhibitors of ALDH2*1 result in reduced acetaldehyde oxidation leading to increased free acetaldehyde. ALDH

alleles (ADH2*2 and ADH3*1) which are more rapidly acting alleles increase the production of acetaldehyde during periods of excess alcohol availability.

Microbial production of acetaldehyde via alcohol oxidation or microbial metabolism leads to increased free acetaldehyde. Those tissues with a high AD-

H:ALDH ratios, such as the oesophagus, are predisposed to having increased free acetaldehyde levels and increased risk of development of pathology such

as neoplasm. The levels of xenobiotics degraded by the same system will also result in increases of similar xeno-aldehydes within the system which may also

have pathologic potential.

471N.R. McGregor / Alcohol 41 (2007) 469e478


the presence of the ALDH2*2 gene is associated with anincrease in oesophageal neoplasm in those subjects withincreased exposure to alcohol and hence a high level ofacetaldehyde, not unlike seen in the animal experiments.Although acetaldehyde-associated neoplasm in Asians as-sociated with the inactive ALDH2*2 allele is strongly asso-ciated with neoplasm development in heavy drinkers, itsrelevance with acetaldehyde-associated pathology in otherpopulations is not clear.

An alternative method to achieve a higher acetaldehydeconcentration is via an increase in the formation rate of ac-etaldehyde. The rapid ethanol metabolizing ADH allele,ADH3*1/*1, is also associated with increased orolaryngeal,laryngeal, and breast neoplasm (reviewed by Eriksson,2001). Thus, several gene polymorphisms that result inhigher acetaldehyde levels with chronic exposure to alcoholare associated with increased neoplasm risk. Thus, the prin-ciples associated with the increased neoplasm risk in heavydrinking Asian ALDH2*2 carriers may be applicable toother events and factors that increase acetaldehyde in otherpopulations. Other potential mechanisms which could alsoinfluence this risk of neoplasm development are outlined inFig. 2. Thus, the evidence suggests the increased conver-sion of alcohol to acetaldehyde and/or the reduced removalof acetaldehyde may have a significant association with theincidence of acetaldehyde-related neoplasm in all popula-tions even though the mechanisms leading to the increasedacetaldehyde may be different.

Multiple environmental events, such as combined drink-ing and smoking, have been found to synergisticallyincrease both acetaldehyde concentrations as well asneoplasm risk (Homann et al., 2000a, 2000b; Salaspuroand Salaspuro, 2004). These associations are well estab-lished but do not have the same elevated risk levels seenwith the genetic predispositions (Altieri et al., 2005). Envi-ronment-based dietary factors, such as folate, which are de-rived from fruit and vegetables, also have been linked toreductions in alcohole and smoking-related upper digestive

tract neoplasm (Bidoli et al., 2003; Galeone et al., 2006).Interestingly, folate reduces the acetaldehyde productionby bowel microorganisms and may reduce the alcohol in-duced increase in acetaldehyde production (Homannet al., 2000a, 2000b; Pelucchi et al., 2003). Although thereis some debate about the actions of folate on inhibition ofADH, it is noted that lower folate levels do correlate withincreased acetaldehyde levels in the colon but not in thesmall intestine, suggesting a microorganism-related change(Homann et al., 2000a, 2000b). Evidence exists that Japa-nese heterozygote ALDH2*1/2*2 subjects have altered fo-late metabolism reflected in changes in mean corpuscularvolume (Yokoyama et al., 2005b). Thus, an array of envi-ronmental factors are associated with increased acetalde-hyde levels and also increased neoplasm risk. However,more studies are required to unravel these findings andhow they relate to the genetic polymorphisms.

ADH:ALDH ratios and tissue neoplasm risk

The variation in the relative amounts of ADH andALDH enzymes within a tissue appear significant in therisk of development of acetaldehyde-related neoplasm. Inthe mouth, the prevalence of gingival/alveolar ridge squa-mous cell carcinoma is 12% of all oral neoplasms and thetissue has an ADH:ALDH ratio of 1, whereas the tongue,which has a ADH:ALDH ratio of 1.3, is approximately50% of all oral neoplasm cases. The oesophagus has anADH:ALDH ratio of 2.8 and has a very high incidence of

0

10

20

30

40

50

60

70

80

90

100

8.8 31.4 41.2 15.7

32.7 44.2 15.4 5.8

100 0 0 0

Never Light Moderate Heavy

ALDH2*1

ALDH2*1/2*2

ALDH2*2

Fig. 3. Alcohol drinking behavior of Japanese men in relationship to ALDH2 genotype (from Yokoyama et al., 2003). Those subjects with homozygote

ALDH2*2 did not drink; those with the heterozygote ALDH2*1/2*2 drank to a lesser degree than those who were homozygote ALDH2*1.

Table 2

OR of the risk of developing oesophageal carcinoma in relationship

to alcohol consumption and ALDH type (from Yang et al., 2005)

ALDH type

Moderate drinking

OR (95%CL)

Heavy drinking

OR (95%CL)

ALDH2*1 1.88 (.42� 8.37) 4.62 (.93� 23.1)

ALDH2*2/2*1 9.64 (3.23� 28.8) 95.4 (28.7� 317)

ALDH 5 Alcohol dehydrogenase; OR 5 Odds ratio.



neoplasms in Asian populations. Thus, it would appear thatthe levels of ADH and ALDH within a tissue have anequally important role in pathological potential as the car-riage of specific ADH and ALDH allele variants. Furtherstudies are warranted into these specific tissue-based varia-tions of induction of ADH and ALDH upon stimulationwith alcohol, acetaldehyde, and xenobiotics in relationshipto pathological potential of the tissue under metabolic load.

Inhibitors of ALDH and neoplasm

It has been proposed that ALDH2 inhibition by Disulfi-ram and the presence of the ALDH2*2 polymorphicsubjects have a similar outcome (Harada et al., 1982).Inhibition of ALDH2 using Disulfiram (Mays et al.,1998), along with a xenobiotic substance, nitrosodiethyl-amine, resulted in rapid development of oesophageal andnasal cavity neoplasms but not those in liver in mice (Ber-tram et al., 1985; Lijinsky and Reuber, 1980). The use ofDisulfiram or the xenobiotic alone resulted in a significantlysmaller number of neoplasms, which were also restricted tothe oesophagus and nasal cavity. A dose of Disulfiramgiven 2 h before nitrosdiethylamine resulted in significantincreases in nitrosdiethylamine in all tissues but the in-creases were greatest in the oesophagus (Frank et al.,1984) consistent with the altered ADH:ALDH ratio in thattissue. A similar increase in oesophageal neoplasm in ratsoccurred when the rats consumed nitrosdiethylamine andalcohol (de Boer et al., 2004). Other carcinogens along withDisulfiram have been linked with increased breast carci-noma (Cheever et al., 1990). Conversely, Disulfiram hasbeen found to reduce the development and progression ofother neoplasms such as those in the bladder (Fiala, 1977;Irving et al, 1983). Thus, the inhibition of ALDH appearsassociated with development of acetaldehyde-related neo-plasms where the active carcinogen may be an aldehyde de-rivative and it may inhibit carcinogens where the activecarcinogen is the result of the action of ALDH upon thecarcinogen. These data support the hypothesis that compe-tition between ethanol and acetaldehyde with other xenobi-otics being metabolized through the ADH, ALDH pathwayleading to higher xenobiotic aldehydes, may result in an in-crease in potential pathology (Frank et al., 1984; Sladek,2003) and in particular neoplasms in the nasal passages,mouth, and oesophagus. The association with the alteredADH:ALDH ratios in upper aerogastrointestinal tract mu-cosa, previously discussed, may also be a significant meta-bolic factor that influences the neoplasm development inspecific tissues such as the oesophagus.

In Japanese men, alcohol, smoking, and green tea are as-sociated with an increased risk for development of oesopha-geal neoplasm (Ishikawa et al., 2006). Conversely, black teahas been found to be protective of oesophageal neoplasms(Franceschi et al., 1992; Hung et al., 2004). One potentialfactor was that green tea was associated with altered bowel

bacterial metabolism of a dietary phytoestrogen, daidzein,resulting in an increase in one of its metabolites, Equol(Miyanaga et al., 2003). Equol has been linked to a 6.5-foldincrease in premalignant cervical lesions in European fe-males (Hernandez et al., 2004). However, this change inbacterial related product may also be an indicator of alter-ation in acetaldehyde production by the bowel flora. TheDaidzein metabolite, daidzin, is a potent inhibitor ofALDH2 (Gao et al., 2001; Keung et al., 1997; Lin et al.,1996). Daidzein is found in the herb Pueraria lobata, (Oh-wi [Chinese], Kakkon [Japanese], Kalgeun [Korean]) aswell as in soy products. The metabolite Daidzin is formedby bacteria from Daidzein and, therefore, sources of thephytoestrogen. Daidzein and its metabolites may act syner-gistically as with smoking and alcohol leading to an in-crease in the pathological potential of alcohol drinking ifthey are consumed in a chronic manner.

The inhibition of ALDH2 by Daidzein and its relatedisoflavanoids may have the same potential influence uponacetaldehyde-related neoplasm as seen with Disulfiram. Insupport of this contention is the observed association in iso-flavanoid levels and various types of neoplasms within dif-ferent populations. In a Japanese population, the meanserum levels of daizdein are between 240 and 280 mmol/land in the UK population between 12 and 17 mmol/l (Mor-ton et al., 2002). The Japanese population has a high riskrate for oesophageal neoplasms (Yang et al., 2005), whereasin the UK, the rate is low. Conversely, the relationship be-tween isoflavanoid-inhibited neoplasm is reversed whencomparing European and Asian populations (Horn-Rosset al., 2000; Watanabe et al., 2002). One study of Japanesesubjects in a western environment, Hawaii, revealed a posi-tive association between tofu consumption and oesophagealneoplasms (Chyou et al., 1995). Importantly, the prelimi-nary data suggests that populations with high dietaryALDH2 inhibitor consumption are also those with in-creased acetaldehyde-related neoplasm risk. It is also inter-esting to speculate that the Asian population penetration ofthe ALDH2*2 gene has occurred due to the high dietaryconsumption of inhibitors of that enzyme, such as Daid-zein. This may represent a genetic mutation supportedby dietary consumption of a product not unlike that seenwith lactose (Tishkoff et al., 2006). Epidemiological stud-ies on oesophageal neoplasms in the Japanese and Chinesepopulations also reveals increases in certain carcinogensand an increase in alcohol and smoking in the populationsassociated with oesophageal neoplasms. Thus, there ap-pears to be a relationship between dietary consumptionof an ALDH2 inhibitor and the incidence of acetalde-hyde-related neoplasm.

Pueraria radix (Kudzu)

Recently studies using Pueraria lobata to create aver-sion to drinking and reduction of alcohol consumption in



alcoholics have been undertaken and the preliminary datasuggests potentially promising results (Keung and Vallee,1998). These studies are similar to those conducted for an-other ALDH inhibitor, Disulfiram, in which inhibition ofacetaldehyde removal results in the development of moresevere hangover symptoms and hence aversion to drinking.However, other studies suggest an increase in acetaldehydein subjects with certain genotypes may be associated withincreases in euphoric symptoms and a desire to increase al-cohol drinking (Behar et al., 1983). Interestingly, Disulfi-ram has been shown to induce euphoria and a positivedrinking habit in some individuals (Brown et al., 1983; Ha-meedi et al., 1995) and this is reviewed in Eriksson (2001).No studies could be identified that studied the associationbetween Pueraria lobata and euphoria. Thus, although Pu-eraria lobata extracts may produce aversion to drinking insome individuals, they may also contribute to euphoria andincreased drinking in others. Further studies are required tounderstand these potential relationships.

Pueraria radix is a traditional herb used as a medicine inChina since 200 BC. The plant provides two differentherbal components: (1) Pueraria lobata (the root basedextract) and (2) Pueraria flos (the flower based extract).

Pueraria flos is the traditional Chinese hangover remedy,which is usually given in combination with three other herbs(Ginseng radix, Amomi Fructus rotundus, Citri reticulataePericarpium) (Niiho et al., 1989; Yamazaki et al., 2002).Studies on Pueraria flos show that it increases the removalrate of acetaldehyde in both rats and humans after alcoholconsumption (Yamazaki et al., 2002) and reduces the nervoustissue damage induced by ethanol (Jang et al., 2001). The ac-tion of Pueraria flos is potentially consistent with the tradi-tional use suggesting a reduction of both acetaldehyde andhangover symptoms (Bensky et al., 2004).

The root extract, Pueraria lobata, is not traditionallyused for hangover treatment (Keung et al., 1997; Keungand Vallee, 1993). Unlike Pueraria flos, Pueraria lobata in-hibits ALDH2 (Gao et al., 2001, 2003; Heyman et al., 1996;Keung and Vallee, 1993; Lukas et al., 2005), which is con-sistent with the potential mechanisms for the developmentof an aversion to alcohol drinking (Lin et al., 1996) notedin the Asian genotypes. The active ALDH2 inhibitor, Daid-zein, and its related metabolites are produced by the bowelflora from the two major isoflavanoid compounds found inPueraria lobata, namely Daidzin and Pueraria (Choo et al.,2002). Two studies did not find a significant reduction inALDH2; however, both of these had very low sample sizes(n 5 3), the rats were killed only 30 min after ethanol in-gestion and they assessed the alterations in ADH andALDH using NADþ/NADH variation (Lin et al., 1996;Xie et al., 1992) suggesting potential methodological prob-lems with these studies. Thus, the balance of evidence sug-gests that the pharmacological actions of Pueraria flos andPueraria lobata differ in relationship to acetaldehyde me-tabolism and appear consistent with the Chinese materiamedica traditional uses.

The active components in Pueraria lobata inhibitALDH2, by 70% at a tissue concentration of 100 nmol/l(Keung and Vallee, 1993). Daidzein found in soy productswas found to be present in serum with a mean value of90 ng/ml and in breast milk at 600 ng/ml after ingestionof soy milk for 2 weeks (Hargreaves et al., 1999). The nor-mal crude dose of Pueraria lobata is 1.5 g twice daily.However, extracts of the root are normally only 10% ofthe dosage requirement (Bensky et al., 2004; Blumenthalet al., 1998). Thus, extract dosages of 150 mg may givean equivalent level to the raw herb. These therapeutic dosesrepresent a Daidzein dose of approximately 30 mg if thestandard dose is given (Fang et al., 2006). A study of inges-tion of 150 mg of isoflavanoids in prostate cancer patientsrevealed a peak plasma level of Daidzein between 1.5and 12 h postingestion of 3.9 6 .3 mmol/l (Miltyk et al.,2003). A study of the pharmacodynamics of soy isoflava-noid ingestions revealed a peak serum level between 4.5and 6 h and a half life of 3e8 h (Shelnutt et al., 2002).Thus, dosages of 30 mg Daidzein would be likely to gaina peak plasma level of 0.78 mmol/l which would be presentfor at least 5 h after ingestion. A dietary supplement studyof 202 Japanese subjects revealed that ingestion of 14 mg ofdietary associated Daidzein per day resulted in a mean se-rum concentration of 119.9 nmol/l (Yamamoto et al., 2001).Another study compared the circulating concentrations ofDaidzein in Japanese and UK men and women (Mortonet al., 2002). In this study, the serum Daidzein levels werebetween 246 and 282 nmol/l for Japanese females andmales, respectively, and only 12.5 and 17.9 nmol/l for UKfemales and males, respectively. These data show that thelevels of Daidzein when consumed as a single supplementor chronically can reach the levels to inhibit ALDH2 atleast by a factor of 70% of normal activity.

Analysis of the supplementation of Daidzein-containingsoy milk was undertaken in rats and the levels of variousalcohol-related measures assessed (Kano et al., 2002). Thisstudy was claimed to show a beneficial effect of soy andfermented soy on reductions in alcohol levels and potentialuse as a protective process as the levels of the cytochromep450 and of the MEOs system were reduced with controlsbut increased compared with untreated rats. The phytoes-trogen, genistein, is found in soy milk and is a knownMEOS inhibitor (Chae et al., 1991) but is not found in Pu-eraria lobata. Analysis of the ratios of the ADH:ALDH2and ADH:ALDH1/3 ratios, in untreated (8.9% sucrose)and three additional groups fed either 5% ethanol (5%E)or 5%E with either soy milk or fermented soy milk, was un-dertaken from the data presented in the study. In the un-treated group, the ratio of ADH:ALDH2 was 3.9, whereasthe ADH:ALDH1/3 was around 1.8. In the control rats,fed5%E, the ADH:ALDH2 ratio leapt to 10.6 whereas theADH:ALDH1/3 ratio was 8.9 [see Table 3]. With the con-sumption of daidzein containing soy milk, these ratios werequite different with the ADH:ALDH2 ratio still increasingbut only to 60% of that of the 5%E controls. With the



fermented soy milk, the ADH:ALDH2 ratio was also about60% of that seen in the controls whereas the ADH:ALDH1/3 was also low compared with the 5%E controls. However,the ADH:ALDH1/3 ratios were much higher in the soy sup-plemented mice. These data suggest that the soy milk notonly inhibited the degree of upregulation MEO activitybut also deregulated the ADH:ALDH ratio and this com-bined effect appear related to the contents of daidzein andgenistein. In the control rats, ADH was unregulated toa greater degree than the MEOS system with the ratio ofADH:MEOS reducing by 50% compared with the untreatedratio. The MEOS upregulation was not as great in the gen-istein containing soy and fermented soy groups. No assess-ment of the changes in oesophageal, nasal, or oral mucosawere evaluated. This suggests an increased potential foracetaldehyde accumulation in selected tissues such as theoesophagus in subjects using daidzein containing dietarycomponents but further studies are required to understandthese potentially important relationships.

In summary, the inhibition of ALDH2 by Pueraria loba-ta components has the same potential influence upon acet-aldehyde metabolism as seen with subjects with (1)heterozygote ALDH2*1/ALDH2*2 alleles and (2) subjectswith rapid metabolizing forms of ADH; and is also poten-tially a problem if combined with smoking and/or drinkingalcohol in normal ADH ALDH individuals. In a Japanesepopulation, the mean serum levels of daizdein are between240 and 280 mmol/l and in the UK population, it is between12 and 17 mmol/l (Morton et al., 2002). The Japanese pop-ulation has a high risk rate for oesophageal neoplasms(Yang et al., 2005), whereas in the UK, the rate is low.No studies have evaluated the risk relationships betweenDaidzein and oesophageal or acetaldehyde-related neo-plasm or pathology in alcoholic or smoking subjects. Thus,chronic consumption of Pueraria lobata along with moder-ate to heavy drinking may increase the risk of developmentof acetaldehyde-related neoplasm. In fact, the combineduse of alcohol, smoking, and consumption of Puerarialobata may synergistically increase the risk.

Pueraria lobata and hangover therapies

Recently, in western countries, products containing Pu-eraria lobata have been sold over the counter as a treatmentof hangover. In many of those countries, these products are

registered on the basis that Pueraria lobata is the traditionalChinese hangover treatment yet examination of the Chinesemateria medica would suggest that these claims are poten-tially misleading (Bensky et al., 2004). The balance of ev-idence would suggest that the active components ofPueraria lobata, in the dosage within the remedies, may in-hibit ALDH2 by up to 70%. The dosage instructions on thehangover remedies vary from two to three 250-mg dosesbefore drinking and two 250-mg doses after drinking result-ing in a dosage of 1,250 mg at the time of highest alcoholconsumption. The chronic consumption of these herbalremedies at the time of peak alcohol/acetaldehyde levelswould seem to represent a potentially significant health riskto the public. These products have the potential effect of ex-posing the public, who drink to excess, to pharmacologicalagents that may increase acetaldehyde at a time of en-hanced susceptibility, while drinking. If these hangoverproducts are used chronically they may have the potentialto increase the risk for acetaldehyde-related neoplasm andother acetaldehyde-related disorders.

Suggested guidelines for the use of Pueraria lobata withalcohol

Guidelines for another ALDH inhibitor, Disulfiram, havealready been established and are recommended in the drugreference manuals such as MIMS� (CPDMedia, St. Leo-nards, Sydney, Australia). These recommendations are asfollows of Disulfiram (Drug Antabuse. Website http://www.mims.com.au/):

1. Under all circumstances, patients receiving Disulfirammust not take alcohol or alcohol containing preparations,e.g., certain cough syrups, sauces, vinegar, tonics, foodsprepared with wine, and should even avoid the use ofaftershave lotions and back rubs containing alcohol.2. Disulfiram should never be administered to a patient whois taking alcohol or is in a state of alcoholic intoxication.

Due to the similarity of metabolic activity of Disulfi-ram and Pueraria lobata in relationship to acetaldehydemetabolism, similar limitations should be considered bythe pharmaceutical industry and regulators for Puerarialobata. If these limitations are accepted, then this shouldpreclude the use of Pueraria lobata as a component ofany remedy for alcohol intoxication, hangover, or use with

Table 3

ADH, ALDH, and MEOS levels and the ratios of ADH to ALDH2, ALDH1/3 and MEOS in relationship to the use of a 5%E solution control and 5%E

solutions with soy milk and fermented soy milk (from Kano et al., 2002)

Group ADH ALDH2 ALDH1/3 MEOS ADH:ALDH2 ADH:ALDH1/3 ADH:MEOS

Untreated 11.62 2.97 0.63 0.98 3.9 18.4 11.9

5%E control 11.72 1.11 1.32 2.20 10.6 8.9 5.3

5%Eþ soy 12.31 2 0.8 1.57 6.2 15.4 7.8

5%Eþ fermented soy 12.65 2.2 1.03 1.30 5.8 12.3 9.7

ADH 5 Alcohol dehydrogenase; ALDH 5 Alcohol dehydrogenase; 5%E 5 5% ethanol.



alcohol containing products. This would also suggest thatthe regulatory authorities should not allow hangoverremedy products containing Pueraria lobata to be listedfor use.

Conclusions

Pueraria lobata contains components which inhibitALDH2 and has a very similar activity to that of the knownALDH2 inhibitor, Disulfiram. Inhibition of ALDH2 and thegenetic polymorphism, ALDH2*2, which has lost its activ-ity, are associated with an increased risk of not only acetal-dehyde-associated pathology but also an increased risk ofneoplasms in the oesophagus, oropharynx, and nasal pas-sages. Disulfiram is recommended not to be taken at thesame time as alcohol, by alcohol-intoxicated subjects, orwith alcohol containing products or foods. These same re-strictions should apply to the herb Pueraria lobata. Theuse of Pueraria lobata in hangover remedies would appearto not only be contrary to traditional use but also to repre-sent a significant health risk to the public, particularly withchronic use in subjects who have a higher alcohol/smokingconsumption.

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