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Alcohol 41 (2007) 469e478
INVITED REVIEWS
Pueraria lobata (Kudzu root) hangover remedies and 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 countries. The available data is reviewed to assess if there are any potential concerns in relationship to the development of neoplasm if these products are used chronically. The herb Pueraria has two components that are used as traditional therapies; Pueraria lobata, the root based herb and Pueraria flos, the flower based herb. Both of these herbal components have different traditional claims and constituents. Pueraria flos, which enhances acetaldehyde removal, is the traditional hangover remedy. Conversely, Pueraria lobata is a known inhibitor of mitochondrial aldehyde dehydrogenase (ALDH2) and increases acetaldehyde. Pueraria lobata is being investigated for use as an aversion therapy for alcoholics due to these characteristics. Pueraria lobata is not a traditional hangover therapy yet has been accepted as the registered active component in many of these hangover products. The risk of development of acetaldehyde pathology, including neoplasms, is associated with genetic polymorphism with enhanced alcohol dehydrogenase (ADH) or reduced ALDH activity leading to increased acetaldehyde levels in the tissues. The chronic usage of Pueraria lobata at times of high ethanol consumption, such as in hangover remedies, may predispose subjects to an increased risk of acetaldehyde-related neoplasm and pathology. The guidelines for Disulfiram, an ALDH2 inhibitor, provide a set of guidelines for use with the herb Pueraria lobata. Pueraria lobata appears to be an inappropriate herb for use in herbal hangover remedies as it is an inhibitor of ALDH2. The recommendations for its use should be similar to those for the ALDH2 inhibitor, Disulfiram. Ó 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 aldehyde dehydrogenase (ALDH) (EC.1.2.1.3) are the two enzymes that metabolize alcohol and the pathway is shown in Fig. 1. Both of these enzymes are classified as phase 1 xenobiotic metabolizing enzymes, and this pathway is important for the degradation of a number of drugs, dietary substances, and other environmental agents (Sladek, 2003). Therefore, this metabolic pathway has other important roles in metabolism apart from the degradation of alcohol. Disturbance of the activities of these enzymes and accumulation of the intermediate, acetaldehyde, in the case of ethanol, is likely to have significant consequences to the host. Also of significance is the high level of metabolism of alcohol after acute intoxication may alter the ability of the body to deal with other xenobiotic substances and may lead to the development of pathology, if these exposures occur chronically. * Tel.: þ61-395-096939; fax: þ61-395-009494. E-mail address:
[email protected] (N.R. McGregor) 0741-8329/07/$ e see front matter Ó 2007 Elsevier Inc. All rights reserved. doi: 10.1016/j.alcohol.2007.07.009
Acetaldehyde is a toxic substance and increases are associated with (1) the development of acute alcohol withdrawal symptoms or ‘‘hangover’’ after acute intoxication (Eriksson, 2001); and with chronic exposure; (2) the development of acetaldehyde-related pathology such as pancreatitis and cirrhosis (Chao et al., 2003); and (3) an increased risk for the development of acetaldehyde-related neoplasm (Brooks and Theruvathu, 2005; Burton, 2005; O’Hanlon, 2005; Poschl and Seitz, 2004; Purohit et al., 2005; Visapaa et al., 2004). In the case of alcohol metabolism, any environmental or genetic factor that disturbs this metabolic process may alter the degree of hangover and or the risk of development of acetaldehyde-related neoplasm, liver and pancreatic disease. Recently, a group of commercially available products have appeared in Western societies which are promoted for use with acute alcohol withdrawal or hangover and these contain a herb that inhibits the mitochondrial ALDH (ALDH2) (Keung and Vallee, 1993). The use of this herb, Pueraria lobata or Kudzu, in such a product appears contradictory to the
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Acetaldehyde
Ethanol CH3CH2OH
ADH
CH3CHO
Acetate
ALDH
CH3CHOOH
Fig. 1. The metabolic pathway for alcohol. ADH, Alcohol dehydrogenase; ALDH, Aldehyde dehydrogenase.
traditional claims and may influence not only hangover symptom expression but also risk of acetaldehyde-related disease and neoplasms (Bensky et al., 2004). A review of the literature is undertaken to evaluate the potential effects of ingestion of Pueraria lobata at the same time as ingestion of alcohol and/or smoking and the relationships with potential development of acetaldehyderelated neoplasm. Genetic polymorphic anomalies in the alcohol metabolizing enzymes have been noted to result in accumulation of acetaldehyde and represent a significant disturbance in this xenobiotic removal system and do have pathologic potential. To understand the potential outcomes, in relationship to alcohol, 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 these are reviewed in detail in several papers (Agarwal, 2001; Sladek, 2003). For the purposes of this review, we will restrict our discussion to the first three families of ALDHs as these are the major ethanol metabolismeassociated enzymes in humans. Family one is located in the cytoplasm and termed ALDH1. Family two are the mitochondrial enzymes, ALDH2, and family three are the inducible enzymes and respond to increased xenobiotic challenge (ALDH3) (Agarwal, 2001; Sladek, 2003). Each of these enzymes is a homotetramer of the various isoenzymes. In humans, ALDH2 is the most prominent enzyme involved in alcohol-associated acetaldehyde oxidation (Klyosov et al., 1996). Polymorphism has been noted in all three families with three variants in each of ALDH1 and ALDH2 and seven in ALDH3. The ALDH2*2 variant, which is found in 50% of Asian populations and 40% of South American Indians, has total loss of activity and is the result of a single nucleotide glutamic acid to lysine substitution at the 14th position from the carboxyl terminal (Hempel et al, 1984; Yoshida et al., 1985). The heterozygote ALDH2*1/2*2 subjects have a reduced removal rate of acetaldehyde compared with the normal ALDH2*1 individuals and have higher acetaldehyde levels. Variants in ALDH3 have also been reported and these are higher in European populations (Agarwal, 2001). The outcome of these ALDH variants is that the removal rate of acetaldehyde is reduced resulting in increased acetaldehyde levels. When this system is deregulated, alcohol is metabolized through alternative metabolic systems such as cytochrome p-450 (Cytochrome p-450 [number
2E1] or Microsomal Ethanol Oxidizing System), the fatty acid 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 salivary glands; ALDH2 is highest in liver, kidney, and eye lens; whereas ALDH3 is highest in stomach mucosa, cornea, breast, lung, oesophagus, and pancreas (Sladek, 2003). Although each of the various ALDHs show alteration in tissue distribution, there are also differences in the ADH:ALDH ratios within tissues which may be a significant reason for the different susceptibilities of those tissues to develop acetaldehyde-related pathology. Table 1 shows the relative variation of ADH and ALDH and the ADH:ALDH ratios within the various upper gastrointestinal tract sites (Dong et al., 1996; Yin et al., 1993). The oesophagus would potentially have the highest concentrations of acetaldehyde after ethanol ingestion as it metabolizes the conversion of ethanol to acetaldehyde at a more rapid rate than it removes acetaldehyde. This pattern of ADH:ALDH, with a lack of ALDH2, appears to be consistent with that of skin (Cheung et al., 1999). This ADH:ALDH ratio variation is well demonstrated when comparing stomach and oesophagus, where the oesophageal epithelium has a four-fold higher induction of ADH compared with the stomach, yet has an 80% reduction in ALDH expression compared with the stomach with the same ethanol and acetaldehyde stimuli (Yin et al., 1993). Thus, tissue variation in the induction of ADH and ALDH may have a significant bearing on the susceptibility of various tissues to develop acetaldehyde-related pathology.
ALDH, acetaldehyde, and pathology A mechanistic outline has been proposed in Fig. 2 for alcohol increased acetaldehyde and its related potential pathology (Frank et al., 1984; Homann et al., 1997). Carriage of the inactive ALDH2*2 results in higher tissue acetaldehyde levels. Microbial action has been linked to increased alcohol-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 Tongue Esophagus Stomach
1 0.4 5.4 1.6
1 0.3 2.2 5.6
1.0 1.3 2.5 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.
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ALDH2*2 Alleles
ALDH Alleles
Acetaldehyde Oxidation
ALDH inhibitors
471
Smoking Acetaldehyde
Pathology
Microbial Activity
Alcohol Oxidation
Tissue ADH:ALDH ratio
AHD2*2 & ADH3*1 Alleles Fig. 2. Mechanistic pathways for increasing acetaldehyde and risk of neoplasm in relationship to ethanol metabolism. The presence of alcohol dehydrogenase 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 ADH: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.
gastrointestinal tract (Homann et al., 2001) and the bowel (Homann et al., 2000a, 2000b). Several compounds are known to inhibit ALDH and lead to increased acetaldehyde levels (Hart and Faiman, 1995). Rapid metabolizing forms of ADH and inhibited ALDH will also result in higher acetaldehyde levels. In a similar mode, the tissue differences in ADH:ALDH ratios also are an important aspect of the selective tissue damage associated with the development of acetaldehyde-related pathology (see Table 1). Smoking is known to increase salivary acetaldehyde and this appears to occur synergistically with both the alcohol-related and microbialrelated increases in acetaldehyde (Homann et al., 2000a, 2000b). Thus, the development of increased acetaldehyde may result from multiple different mechanisms and occur at different levels within various tissues. Homozygote ALDH2*2 subjects rarely drink and have aversion to drinking due to the severity of acute alcohol intoxicationeinduced symptoms associated with increased acetaldehyde levels. However some heterozygote ALDH2*1/ 2*2 subjects do drink, although this is at lower rates than ALDH2*1 subjects (see Fig. 3) (Yokoyama et al., 2003). In recent years, there has been an increase in drinking within the Japanese population; in 1979, 2.5% of alcoholics were heterozygote for ALDH2, in 1986, it was 8.0%, and in 1992, it was 13.0% (Higuchi et al., 1996). Analysis of the reasons for this increase in alcoholic ALDH2 heterozygote Japanese men was not found to be based upon the same alcohol dependence/abuse characteristics seen in the homozygote ALDH2*1 subjects (Takeshita et al., 1998). The ALDH2*2/2*2 homozygote, if they were drinkers, drink larger quantities of alcohol and did so habitually (Okamoto et al., 2001). This drinking behavior displayed by the ALDH2*2 subjects may be the same as seen in Caucasian
subjects, where continual drinking is apparently used to relieve symptoms (Earleywine, 1993a, 1993b; Span and Earleywine, 1999) or alternatively, the drinking may be related to the development of euphoria. This drinking-related euphoria has been documented in some individuals taking the ALDH inhibitor, Disulfiram (Brown et al., 1983). Increased acetaldehyde exposure due to increased drinking may increase the risk of development of acetaldehyde-related pathology (Brennan et al., 2004). Thus, the carriage of ALDH2*2 or inhibitors of ALDH2 are associated with increased drinking in up to 13% of carrier subjects and this may be related to increased euphoria or the need to reduce alcohol intoxication hangover symptoms.
ALDH, acetaldehyde, and neoplasm Asian subjects who are homozygote for ALDH2*2 have a reduced rate of neoplasm and the majority have an aversion to drinking alcohol (Eriksson, 2001; Yokoyama et al., 2005a). However, the homozygote ALDH2*2 subjects, who do drink, drink to a greater level than those who are homozygote for ALDH2*1 (Okamoto et al., 2001) and have a dramatic increase in risk for the development of acetaldehyde-related neoplasm (Yokoyama et al., 1996b). Subjects with ALDH2*1/2*2 also have an increased risk of developing acetaldehyde-related neoplasm (Hori et al., 1997; Yokoyama et al., 1996a, 1998, 1996c). Table 2 shows the odds ratios for oesophageal neoplasm in alcoholic subjects related to their drinking levels and their ALDH2 gene alleles (Yang et al., 2005). One study suggests that high alcohol consumption and the ALDH2*2 gene are also related to an increase in rectal neoplasm (Matsuo et al., 2002). Thus,
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N.R. McGregor / Alcohol 41 (2007) 469e478 100 90 80 70 60 50 40 30 20 10 0
Never
Light
Moderate
Heavy
ALDH2*1 ALDH2*1/2*2
8.8 32.7
31.4 44.2
41.2 15.4
15.7 5.8
ALDH2*2
100
0
0
0
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.
the presence of the ALDH2*2 gene is associated with an increase in oesophageal neoplasm in those subjects with increased exposure to alcohol and hence a high level of acetaldehyde, not unlike seen in the animal experiments. Although acetaldehyde-associated neoplasm in Asians associated with the inactive ALDH2*2 allele is strongly associated with neoplasm development in heavy drinkers, its relevance with acetaldehyde-associated pathology in other populations is not clear. An alternative method to achieve a higher acetaldehyde concentration is via an increase in the formation rate of acetaldehyde. 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 in higher acetaldehyde levels with chronic exposure to alcohol are associated with increased neoplasm risk. Thus, the principles associated with the increased neoplasm risk in heavy drinking Asian ALDH2*2 carriers may be applicable to other events and factors that increase acetaldehyde in other populations. Other potential mechanisms which could also influence this risk of neoplasm development are outlined in Fig. 2. Thus, the evidence suggests the increased conversion of alcohol to acetaldehyde and/or the reduced removal of acetaldehyde may have a significant association with the incidence of acetaldehyde-related neoplasm in all populations even though the mechanisms leading to the increased acetaldehyde may be different. Multiple environmental events, such as combined drinking and smoking, have been found to synergistically increase both acetaldehyde concentrations as well as neoplasm risk (Homann et al., 2000a, 2000b; Salaspuro and Salaspuro, 2004). These associations are well established but do not have the same elevated risk levels seen with the genetic predispositions (Altieri et al., 2005). Environment-based dietary factors, such as folate, which are derived from fruit and vegetables, also have been linked to reductions in alcohole and smoking-related upper digestive
tract neoplasm (Bidoli et al., 2003; Galeone et al., 2006). Interestingly, folate reduces the acetaldehyde production by bowel microorganisms and may reduce the alcohol induced increase in acetaldehyde production (Homann et al., 2000a, 2000b; Pelucchi et al., 2003). Although there is some debate about the actions of folate on inhibition of ADH, it is noted that lower folate levels do correlate with increased acetaldehyde levels in the colon but not in the small intestine, suggesting a microorganism-related change (Homann et al., 2000a, 2000b). Evidence exists that Japanese heterozygote ALDH2*1/2*2 subjects have altered folate metabolism reflected in changes in mean corpuscular volume (Yokoyama et al., 2005b). Thus, an array of environmental factors are associated with increased acetaldehyde levels and also increased neoplasm risk. However, more studies are required to unravel these findings and how they relate to the genetic polymorphisms. ADH:ALDH ratios and tissue neoplasm risk The variation in the relative amounts of ADH and ALDH enzymes within a tissue appear significant in the risk of development of acetaldehyde-related neoplasm. In the mouth, the prevalence of gingival/alveolar ridge squamous cell carcinoma is 12% of all oral neoplasms and the tissue has an ADH:ALDH ratio of 1, whereas the tongue, which has a ADH:ALDH ratio of 1.3, is approximately 50% of all oral neoplasm cases. The oesophagus has an ADH:ALDH ratio of 2.8 and has a very high incidence of 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 ALDH2*2/2*1
1.88 (.42 8.37) 9.64 (3.23 28.8)
4.62 (.93 23.1) 95.4 (28.7 317)
ALDH 5 Alcohol dehydrogenase; OR 5 Odds ratio.
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neoplasms in Asian populations. Thus, it would appear that the levels of ADH and ALDH within a tissue have an equally important role in pathological potential as the carriage of specific ADH and ALDH allele variants. Further studies are warranted into these specific tissue-based variations of induction of ADH and ALDH upon stimulation with alcohol, acetaldehyde, and xenobiotics in relationship to pathological potential of the tissue under metabolic load.
Inhibitors of ALDH and neoplasm It has been proposed that ALDH2 inhibition by Disulfiram and the presence of the ALDH2*2 polymorphic subjects have a similar outcome (Harada et al., 1982). Inhibition of ALDH2 using Disulfiram (Mays et al., 1998), along with a xenobiotic substance, nitrosodiethylamine, resulted in rapid development of oesophageal and nasal cavity neoplasms but not those in liver in mice (Bertram et al., 1985; Lijinsky and Reuber, 1980). The use of Disulfiram or the xenobiotic alone resulted in a significantly smaller number of neoplasms, which were also restricted to the oesophagus and nasal cavity. A dose of Disulfiram given 2 h before nitrosdiethylamine resulted in significant increases in nitrosdiethylamine in all tissues but the increases were greatest in the oesophagus (Frank et al., 1984) consistent with the altered ADH:ALDH ratio in that tissue. A similar increase in oesophageal neoplasm in rats occurred when the rats consumed nitrosdiethylamine and alcohol (de Boer et al., 2004). Other carcinogens along with Disulfiram have been linked with increased breast carcinoma (Cheever et al., 1990). Conversely, Disulfiram has been found to reduce the development and progression of other neoplasms such as those in the bladder (Fiala, 1977; Irving et al, 1983). Thus, the inhibition of ALDH appears associated with development of acetaldehyde-related neoplasms where the active carcinogen may be an aldehyde derivative and it may inhibit carcinogens where the active carcinogen is the result of the action of ALDH upon the carcinogen. These data support the hypothesis that competition between ethanol and acetaldehyde with other xenobiotics being metabolized through the ADH, ALDH pathway leading to higher xenobiotic aldehydes, may result in an increase in potential pathology (Frank et al., 1984; Sladek, 2003) and in particular neoplasms in the nasal passages, mouth, and oesophagus. The association with the altered ADH:ALDH ratios in upper aerogastrointestinal tract mucosa, previously discussed, may also be a significant metabolic factor that influences the neoplasm development in specific tissues such as the oesophagus. In Japanese men, alcohol, smoking, and green tea are associated with an increased risk for development of oesophageal neoplasm (Ishikawa et al., 2006). Conversely, black tea has been found to be protective of oesophageal neoplasms (Franceschi et al., 1992; Hung et al., 2004). One potential factor was that green tea was associated with altered bowel
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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-fold increase in premalignant cervical lesions in European females (Hernandez et al., 2004). However, this change in bacterial related product may also be an indicator of alteration in acetaldehyde production by the bowel flora. The Daidzein metabolite, daidzin, is a potent inhibitor of ALDH2 (Gao et al., 2001; Keung et al., 1997; Lin et al., 1996). Daidzein is found in the herb Pueraria lobata, (Ohwi [Chinese], Kakkon [Japanese], Kalgeun [Korean]) as well as in soy products. The metabolite Daidzin is formed by bacteria from Daidzein and, therefore, sources of the phytoestrogen. Daidzein and its metabolites may act synergistically as with smoking and alcohol leading to an increase in the pathological potential of alcohol drinking if they are consumed in a chronic manner. The inhibition of ALDH2 by Daidzein and its related isoflavanoids may have the same potential influence upon acetaldehyde-related neoplasm as seen with Disulfiram. In support of this contention is the observed association in isoflavanoid levels and various types of neoplasms within different populations. In a Japanese population, the mean serum levels of daizdein are between 240 and 280 mmol/l and in the UK population between 12 and 17 mmol/l (Morton et al., 2002). The Japanese population has a high risk rate for oesophageal neoplasms (Yang et al., 2005), whereas in the UK, the rate is low. Conversely, the relationship between isoflavanoid-inhibited neoplasm is reversed when comparing European and Asian populations (Horn-Ross et al., 2000; Watanabe et al., 2002). One study of Japanese subjects in a western environment, Hawaii, revealed a positive association between tofu consumption and oesophageal neoplasms (Chyou et al., 1995). Importantly, the preliminary data suggests that populations with high dietary ALDH2 inhibitor consumption are also those with increased acetaldehyde-related neoplasm risk. It is also interesting to speculate that the Asian population penetration of the ALDH2*2 gene has occurred due to the high dietary consumption of inhibitors of that enzyme, such as Daidzein. This may represent a genetic mutation supported by dietary consumption of a product not unlike that seen with lactose (Tishkoff et al., 2006). Epidemiological studies on oesophageal neoplasms in the Japanese and Chinese populations also reveals increases in certain carcinogens and an increase in alcohol and smoking in the populations associated with oesophageal neoplasms. Thus, there appears to be a relationship between dietary consumption of an ALDH2 inhibitor and the incidence of acetaldehyde-related neoplasm.
Pueraria radix (Kudzu) Recently studies using Pueraria lobata to create aversion to drinking and reduction of alcohol consumption in
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alcoholics have been undertaken and the preliminary data suggests potentially promising results (Keung and Vallee, 1998). These studies are similar to those conducted for another ALDH inhibitor, Disulfiram, in which inhibition of acetaldehyde removal results in the development of more severe hangover symptoms and hence aversion to drinking. However, other studies suggest an increase in acetaldehyde in subjects with certain genotypes may be associated with increases in euphoric symptoms and a desire to increase alcohol drinking (Behar et al., 1983). Interestingly, Disulfiram has been shown to induce euphoria and a positive drinking habit in some individuals (Brown et al., 1983; Hameedi et al., 1995) and this is reviewed in Eriksson (2001). No studies could be identified that studied the association between Pueraria lobata and euphoria. Thus, although Pueraria lobata extracts may produce aversion to drinking in some individuals, they may also contribute to euphoria and increased drinking in others. Further studies are required to understand these potential relationships. Pueraria radix is a traditional herb used as a medicine in China since 200 BC. The plant provides two different herbal components: (1) Pueraria lobata (the root based extract) 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 reticulatae Pericarpium) (Niiho et al., 1989; Yamazaki et al., 2002). Studies on Pueraria flos show that it increases the removal rate of acetaldehyde in both rats and humans after alcohol consumption (Yamazaki et al., 2002) and reduces the nervous tissue damage induced by ethanol (Jang et al., 2001). The action of Pueraria flos is potentially consistent with the traditional use suggesting a reduction of both acetaldehyde and hangover symptoms (Bensky et al., 2004). The root extract, Pueraria lobata, is not traditionally used for hangover treatment (Keung et al., 1997; Keung and Vallee, 1993). Unlike Pueraria flos, Pueraria lobata inhibits ALDH2 (Gao et al., 2001, 2003; Heyman et al., 1996; Keung and Vallee, 1993; Lukas et al., 2005), which is consistent with the potential mechanisms for the development of an aversion to alcohol drinking (Lin et al., 1996) noted in the Asian genotypes. The active ALDH2 inhibitor, Daidzein, and its related metabolites are produced by the bowel flora from the two major isoflavanoid compounds found in Pueraria lobata, namely Daidzin and Pueraria (Choo et al., 2002). Two studies did not find a significant reduction in ALDH2; however, both of these had very low sample sizes (n 5 3), the rats were killed only 30 min after ethanol ingestion and they assessed the alterations in ADH and ALDH using NADþ/NADH variation (Lin et al., 1996; Xie et al., 1992) suggesting potential methodological problems with these studies. Thus, the balance of evidence suggests that the pharmacological actions of Pueraria flos and Pueraria lobata differ in relationship to acetaldehyde metabolism and appear consistent with the Chinese materia medica traditional uses.
The active components in Pueraria lobata inhibit ALDH2, by 70% at a tissue concentration of 100 nmol/l (Keung and Vallee, 1993). Daidzein found in soy products was found to be present in serum with a mean value of 90 ng/ml and in breast milk at 600 ng/ml after ingestion of soy milk for 2 weeks (Hargreaves et al., 1999). The normal crude dose of Pueraria lobata is 1.5 g twice daily. However, extracts of the root are normally only 10% of the dosage requirement (Bensky et al., 2004; Blumenthal et al., 1998). Thus, extract dosages of 150 mg may give an equivalent level to the raw herb. These therapeutic doses represent a Daidzein dose of approximately 30 mg if the standard dose is given (Fang et al., 2006). A study of ingestion of 150 mg of isoflavanoids in prostate cancer patients revealed a peak plasma level of Daidzein between 1.5 and 12 h postingestion of 3.9 6 .3 mmol/l (Miltyk et al., 2003). A study of the pharmacodynamics of soy isoflavanoid ingestions revealed a peak serum level between 4.5 and 6 h and a half life of 3e8 h (Shelnutt et al., 2002). Thus, dosages of 30 mg Daidzein would be likely to gain a peak plasma level of 0.78 mmol/l which would be present for at least 5 h after ingestion. A dietary supplement study of 202 Japanese subjects revealed that ingestion of 14 mg of dietary associated Daidzein per day resulted in a mean serum concentration of 119.9 nmol/l (Yamamoto et al., 2001). Another study compared the circulating concentrations of Daidzein in Japanese and UK men and women (Morton et al., 2002). In this study, the serum Daidzein levels were between 246 and 282 nmol/l for Japanese females and males, respectively, and only 12.5 and 17.9 nmol/l for UK females and males, respectively. These data show that the levels of Daidzein when consumed as a single supplement or chronically can reach the levels to inhibit ALDH2 at least by a factor of 70% of normal activity. Analysis of the supplementation of Daidzein-containing soy milk was undertaken in rats and the levels of various alcohol-related measures assessed (Kano et al., 2002). This study was claimed to show a beneficial effect of soy and fermented soy on reductions in alcohol levels and potential use as a protective process as the levels of the cytochrome p450 and of the MEOs system were reduced with controls but increased compared with untreated rats. The phytoestrogen, genistein, is found in soy milk and is a known MEOS inhibitor (Chae et al., 1991) but is not found in Pueraria lobata. Analysis of the ratios of the ADH:ALDH2 and 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 undertaken from the data presented in the study. In the untreated group, the ratio of ADH:ALDH2 was 3.9, whereas the ADH:ALDH1/3 was around 1.8. In the control rats, fed5%E, the ADH:ALDH2 ratio leapt to 10.6 whereas the ADH:ALDH1/3 ratio was 8.9 [see Table 3]. With the consumption of daidzein containing soy milk, these ratios were quite different with the ADH:ALDH2 ratio still increasing but only to 60% of that of the 5%E controls. With the
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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 5%E control 5%E þ soy 5%E þ fermented soy
11.62 11.72 12.31 12.65
2.97 1.11 2 2.2
0.63 1.32 0.8 1.03
0.98 2.20 1.57 1.30
3.9 10.6 6.2 5.8
18.4 8.9 15.4 12.3
11.9 5.3 7.8 9.7
ADH 5 Alcohol dehydrogenase; ALDH 5 Alcohol dehydrogenase; 5%E 5 5% ethanol.
fermented soy milk, the ADH:ALDH2 ratio was also about 60% 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 supplemented mice. These data suggest that the soy milk not only inhibited the degree of upregulation MEO activity but also deregulated the ADH:ALDH ratio and this combined effect appear related to the contents of daidzein and genistein. In the control rats, ADH was unregulated to a greater degree than the MEOS system with the ratio of ADH:MEOS reducing by 50% compared with the untreated ratio. The MEOS upregulation was not as great in the genistein containing soy and fermented soy groups. No assessment of the changes in oesophageal, nasal, or oral mucosa were evaluated. This suggests an increased potential for acetaldehyde accumulation in selected tissues such as the oesophagus in subjects using daidzein containing dietary components but further studies are required to understand these potentially important relationships. In summary, the inhibition of ALDH2 by Pueraria lobata components has the same potential influence upon acetaldehyde metabolism as seen with subjects with (1) heterozygote ALDH2*1/ALDH2*2 alleles and (2) subjects with rapid metabolizing forms of ADH; and is also potentially a problem if combined with smoking and/or drinking alcohol in normal ADH ALDH individuals. In a Japanese population, the mean serum levels of daizdein are between 240 and 280 mmol/l and in the UK population, it is between 12 and 17 mmol/l (Morton et al., 2002). The Japanese population 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 between Daidzein and oesophageal or acetaldehyde-related neoplasm or pathology in alcoholic or smoking subjects. Thus, chronic consumption of Pueraria lobata along with moderate to heavy drinking may increase the risk of development of acetaldehyde-related neoplasm. In fact, the combined use of alcohol, smoking, and consumption of Pueraria lobata may synergistically increase the risk.
Pueraria lobata and hangover therapies Recently, in western countries, products containing Pueraria lobata have been sold over the counter as a treatment of hangover. In many of those countries, these products are
registered on the basis that Pueraria lobata is the traditional Chinese hangover treatment yet examination of the Chinese materia medica would suggest that these claims are potentially misleading (Bensky et al., 2004). The balance of evidence would suggest that the active components of Pueraria lobata, in the dosage within the remedies, may inhibit ALDH2 by up to 70%. The dosage instructions on the hangover remedies vary from two to three 250-mg doses before drinking and two 250-mg doses after drinking resulting in a dosage of 1,250 mg at the time of highest alcohol consumption. The chronic consumption of these herbal remedies at the time of peak alcohol/acetaldehyde levels would seem to represent a potentially significant health risk to the public. These products have the potential effect of exposing the public, who drink to excess, to pharmacological agents that may increase acetaldehyde at a time of enhanced susceptibility, while drinking. If these hangover products are used chronically they may have the potential to increase the risk for acetaldehyde-related neoplasm and other acetaldehyde-related disorders.
Suggested guidelines for the use of Pueraria lobata with alcohol Guidelines for another ALDH inhibitor, Disulfiram, have already been established and are recommended in the drug reference manuals such as MIMSÔ (CPDMedia, St. Leonards, Sydney, Australia). These recommendations are as follows of Disulfiram (Drug Antabuse. Website http:// www.mims.com.au/): 1. Under all circumstances, patients receiving Disulfiram must not take alcohol or alcohol containing preparations, e.g., certain cough syrups, sauces, vinegar, tonics, foods prepared with wine, and should even avoid the use of aftershave lotions and back rubs containing alcohol. 2. Disulfiram should never be administered to a patient who is taking alcohol or is in a state of alcoholic intoxication. Due to the similarity of metabolic activity of Disulfiram and Pueraria lobata in relationship to acetaldehyde metabolism, similar limitations should be considered by the pharmaceutical industry and regulators for Pueraria lobata. If these limitations are accepted, then this should preclude the use of Pueraria lobata as a component of any remedy for alcohol intoxication, hangover, or use with
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alcohol containing products. This would also suggest that the regulatory authorities should not allow hangover remedy products containing Pueraria lobata to be listed for use.
Conclusions Pueraria lobata contains components which inhibit ALDH2 and has a very similar activity to that of the known ALDH2 inhibitor, Disulfiram. Inhibition of ALDH2 and the genetic polymorphism, ALDH2*2, which has lost its activity, are associated with an increased risk of not only acetaldehyde-associated pathology but also an increased risk of neoplasms in the oesophagus, oropharynx, and nasal passages. Disulfiram is recommended not to be taken at the same time as alcohol, by alcohol-intoxicated subjects, or with alcohol containing products or foods. These same restrictions should apply to the herb Pueraria lobata. The use of Pueraria lobata in hangover remedies would appear to not only be contrary to traditional use but also to represent a significant health risk to the public, particularly with chronic use in subjects who have a higher alcohol/smoking consumption.
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