Kudzu (Pueraria lobata) – Botany, Therapeutic Uses, Constituents, Pharmaco, Adverse Effects

A perennial, kudzu is a rapidly growing, climbing vine. Native to southern Japan and southeastern China, the name is derived from Kuzo, the Japanese designation for this species. In China the root preparation is referred to as Ge Gen. The plant was first introduced into the United States by the Japanese during the 1876 Philadelphia World’s Fair. It has been referred to as porch vine because of its ability to climb a trellis quickly and produce shade. Other informal appellations include “foot-a-night vine” and “the vine that ate the South,” which also refer to its rapid and aggressive growth. Its cultivation in the United States was encouraged in the first half of the twentieth century for use as fodder and to reduce soil erosion. As the climate in the southeastern United States is ideal for its growth and propagation, kudzu spread extensively throughout the region and is now considered by many to be a noxious weed. The density of kudzu vine can be great enough in forests to prevent tree growth.

Kudzu has for centuries been employed for a number of uses. These range from soups, lotions, teas, and juices to fabrics, starches, and furniture. It is now being recommended as a biofuel. Kudzu flowers, leaves, and roots have for some time been consumed in Asia for treating a variety of ailments, including cancer, headaches, cardiovascular conditions, respiratory problems, hay fever, psoriasis, migraine headaches, and diabetes. With regard to central nervous system disorders, more than 1,000 years ago the Chinese reported its possible value as a treatment for alcoholism and for the symptoms of alcohol hangover. Pharmacological studies have yet to demonstrate whether this purported benefit is due to a direct effect on the brain or is secondary to an effect on alcohol absorption or metabolism. More recent work suggests kudzu may have neuroprotective properties. If so, it may be a potential therapy for minimizing the brain damage associated with a stroke, and perhaps in slowing the brain cell death responsible for Alzheimer’s, Parkinson’s, and other neurodegenerative disorders. Given these possibilities, a critical assessment of the pharmacological properties and central nervous system effects of kudzu is warranted.

Botany

As the aerial parts of the kudzu plant die in cold weather and prolonged freezing can be fatal for the roots, this plant is most commonly found in warmer regions, such as the southern United States. While kudzu is native to much of the southern Asian continent and associated islands, fossil plants of the genus Pueraria are also located in temperate regions of Eurasia. Diversification of the Pueraria species throughout Asia and Oceania appears to have begun in the mid-Miocene epoch, or about 12 million years ago. The Miocene was characterized by a relatively warm global climate.

Kudzu reproduces by either seed or vegetative means. With the latter, the vine shoots spread horizontally from the root crown. During the growing season portions of the root system swell and form edible, starch-filled tubers. These tubers are sometimes ingested for medicinal purposes.

There may be up to 17 species of kudzu, although its taxonomy is a matter of debate. In one system there is only a single name for kudzu, Pueraria lobata. In another, the species lobata is one of three varieties of Pueraria montana. The other two are Pueraria chinensis and montana. In this system, Pueraria montana (Lour.) Merr. var. lobata (Willd.) Maesen and Almeida is the scientific designation for the cultivar found in the United States. The taxonomic classification does not, however, reflect any differences in plant constituents believed to be responsible for therapeutic activity. All species produce the same substances. Quantitatively, however, their concentrations vary within, as well as between, cultivars.

The genus Pueraria belongs to the legume family, Leguminosae. The Leguminosae encompass a variety of plants, including common peas and beans. Their characteristic flower is well-designed for insect pollination. Both the soy bean (Glycine max) and kudzu belong to Glycininae, a subgroup of the Leguminosae. All members of this family produce isoflavones, chemicals thought to be responsible in part for their therapeutic benefits.

Therapeutic Uses

Kudzu has for centuries been a staple among Chinese herbal medicines. The sixteenth century manual of medicinal herbs by Shih-Chen Li recommends the root be used for its antipyretic and antiemetic actions, and as a treatment for poisoning. Kudzu seeds and flowers were prescribed for ailments associated with alcoholic excess, and the leaves applied to wounds to facilitate healing.

A treatise on modern Chinese herbal therapy includes a list of recommended uses for kudzu root. Because it reportedly decreases vascular resistance, it is recommended as a treatment for hypertension and for increasing blood flow to the heart and brain. The vascular effect might also explain its reported efficacy in minimizing tissue damage associated with cardiac and cerebral infarcts. Kudzu is also recommended as a treatment for cancer, for osteoporosis, and migraine headaches. Recently there has been a renewed interest in the historic use of kudzu as a remedy for hangover and alcoholism. This has led to a number of published reports on the effectiveness of kudzu preparations, and individual isoflavones isolated from the plant, in reducing alcohol consumption and the symptoms associated with alcohol withdrawal. Included among these are studies on possible biochemical effects of kudzu that may be responsible for its various therapeutic actions.

Constituents

As with all plants, kudzu flowers, leaves, and roots contain scores of different chemical agents. To date, those in kudzu thought to be the most bioactive are certain isoflavones and their glycosides. A glycoside is a noncarbohydrate molecule bound to a sugar moiety. In this case, the isoflavone is the noncarbohydrate portion of the molecule. The term aglycone is used to describe the noncarbohydrate portion of the molecule after removal of the sugar moiety. More than 20 different isoflavone glycosides and aglycones have been identified in kudzu extracts. Those generating the greatest interest as possible therapeutics are the glycosides puerarin, daidzin, and genistin, and the aglycones daidzein and genistein.

The relative percentages of the various isoflavones and isoflavone glycosides vary in different cultures of kudzu.8 In the root of the Pueraria lobata found in the United States, puerarin is present in higher concentrations than the other isoflavone glycosides and the aglycones. A study of 96 samples of kudzu collected at different times of the year revealed that the roots of three-year-old plants harvested in January have the highest content of isoflavonoids. The degree of variation adds to the difficulty in ensuring consistency of content in kudzu products sold commercially. It also complicates interpretation of laboratory results obtained using unpurified plant extracts or powders. As the kudzu isoflavones have been chemically synthesized, it is possible to obtain pure samples for studying the pharmacological properties of these compounds. This makes it much easier for laboratories to reproduce findings by eliminating the variability that accompanies the use of extracts or plant products from different cultivars that may have been harvested at different times of the year.

As a group, the kudzu flavonoids are considered phytoestrogens. This term is used to describe plant products that display estrogenic activity. Estrogen is the primary female sex hormone. While structurally different from estrogen, phytoestrogens are capable of stimulating or blocking estrogen receptors. Given this property, such agents can induce or inhibit estrogenic effects. Such actions could explain, in part, some of the medicinal benefits attributed to kudzu.

Pharmacokinetics

Studies have been conducted on the absorption, organ distribution, and metabolism of the chemical constituents in kudzu extracts, with particular emphasis on the isoflavone components. The results vary depending on the animal species studied, route of administration, source of the extract, and method of analysis. In general, the data indicate that the kudzu isoflavones, both the glycosides and aglycones, are absorbed to a limited extent following oral administration and are rapidly eliminated. For example, blood levels of puerarin in the rat following oral administration are maximal in less than an hour, with the half-life for elimination being less than two hours. In humans, however, the time for attaining maximum blood levels ranged from five to nine hours for the various glycosides and aglycones, with the half-lives for elimination averaging six hours. Absorption appears to be due to both passive diffusion and carrier-mediated transport. It has also been found that some of these isoflavones are metabolized by intestinal bacteria to agents displaying estrogenic activity, such as equol, and that the parent isoflavone may be converted to other metabolic products in their initial passage through the liver. This rapid biotransformation is one reason for their relatively low and variable bioavailability.

Attempts have been made to enhance absorption of certain isoflavones by modifying the vehicle used for administration of purified substances. These approaches, which include use of phospholipid complexes or nanoparticles, tend to increase the extent of absorption and the isoflavone concentrations in various organs.

The most precise pharmacokinetic data on the chemical components of kudzu are obtained using chemically pure isoflavones. Plant extracts, such as those contained in consumer products, are less useful for such studies given the high degree of variation in the concentration of constituents among these preparations. This variability makes it difficult to know the amount of any particular chemical being administered. On the other hand, the use of pure chemicals makes it impossible to know whether other components of the extract influence the rate and extent of absorption, or the metabolism, of individual constituents. Because of this, results with pure compounds may not in all cases accurately reflect their pharmacokinetics when they are taken along with the other plant constituents, as is the case with commercial products. In one study a methanol extract was administered to mice, with body fluid measurements indicating the isoflavones were rapidly absorbed and subsequently eliminated to a large extent in urine and feces. Organ tissue analysis 24 hours after administration revealed these compounds were widely distributed throughout the body with the highest concentration in the liver. As none of these compounds was detected in the brain, it was concluded that puerarin, daidzin, and malonyl daidzin do not penetrate into the central nervous system, or are rapidly eliminated from this region of the body. Such data call into question whether isoflavone components of kudzu extracts directly affect the brain.

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Qualitatively similar results were found when studying the absorption, distribution, metabolism, and elimination of puerarin when the purified compound was administered alone to rats. These experiments revealed that puerarin was absorbed into blood following oral administration, reaching its maximum serum concentration within approximately 40 minutes, declining thereafter. In this case the highest concentration of compound was found in the lungs, although some was detected in the brain as well.

The absorption in rats of a mixture of the kudzu aglycones daidzein, genistein, and glycitein has been compared with the absorption of daidzin, genistin, and glycitin, their corresponding glucosides. The results indicate that the oral bioavailability of these agents varies between 8% and 35%, with no consistent differences noted between the glycosides and the aglycones. These data indicate that these isoflavones appear in blood following oral administration, although the bioavailability is limited. The differences between the findings with the pure substance as compared to an extract highlights the difficulties associated with comparing the pharmacokinetic properties of an agent administered alone to when it is given as part of a compound mixture. Inasmuch as kudzu extract is most commonly taken by consumers, results with mixtures more accurately reflect what occurs with normal usage. Such data are inconclusive as to which, if any, of the kudzu isoflavones or their metabolites penetrate into the brain in sufficient quantities and for a sufficient period of time to have any clinically significant effect on central nervous system activity.

Pharmacodynamics

Over the centuries, kudzu has been recommended for treating a host of conditions from cancer to migraine headaches and diabetes. In the ancient literature there is limited mention of this plant preparation having any obvious effect on central nervous system function, and no suggestions it may be of value in treating neurological or psychiatric disorders. Kudzu has, however, been reported to be effective as a treatment for alcoholism and the symptoms associated with alcohol withdrawal. The use of kudzu for these purposes has been documented for more than 1,000 years. A kudzu-induced reduction in alcohol consumption could be due to an effect on the brain that modifies the action of alcohol on the nervous system, or could be the result of an effect of kudzu constituents on the absorption, distribution, or metabolism of alcohol, thereby reducing the amount of ethanol that reaches the brain. In the latter case the kudzu-derived compound would not have to penetrate into the central nervous system to be effective.

It is possible that the ancient Chinese kudzu preparation had somewhat different constituents than those used today. This would make it difficult to draw firm conclusions about the possible beneficial effects of contemporary preparations on the basis of reports originating centuries ago in a different culture. For example, while the early Chinese used preparations of the kudzu flower to treat alcoholism, most products sold today are extracts prepared from the roots. Inasmuch as a metabolite of the isoflavone tectoridin, which is localized to the kudzu flower, protects mice from ethanol-induced liver toxicity, it is possible that the beneficial effect in treating alcoholism is peculiar to the flower preparation. Nonetheless, there has been a renewed interest in the possible use of kudzu to treat alcoholism and alcohol withdrawal, with studies performed to determine whether root constituents have such an effect and, if so, to define the mechanism of action for this response. Laboratory animal studies show that administration of kudzu extracts, or of purified puerarin or daidzin, isoflavones glycones present in these root extracts, lessens the anxiety associated with alcohol withdrawal and reduces alcohol intake in rats and hamsters conditioned to consume this beverage. In one study an attempt was made to measure brain levels of puerarin in alcohol-preferring rats after administration of the purified isoflavone at a dose that reduces voluntary alcohol intake by 50%. No puerarin was detected in the brain even though its administration had a significant effect on alcohol consumption. This suggests that the antialcohol effect of puerarin, and of possibly the kudzu extract as a whole, is due to an action outside of the central nervous system.

Clinical trials of kudzu root extract have yielded conflicting results with regard to its utility as a therapy for alcoholism. In one pilot study the consumption of 1.2 g of kudzu extract twice daily for a month had no effect on the sobriety or alcohol craving of chronic alcoholics. In contrast, a later study found that administration of kudzu root extract for seven days significantly reduced voluntary alcohol consumption in heavy drinkers. The differences in these findings could be due to the fact that different populations of patients were examined, with in one case the subjects being classified as chronic alcoholics, whereas in the other they were characterized as heavy drinkers. Another explanation could relate to differences in the chemical composition of the kudzu preparations used in these studies, as variations would be anticipated among cultivars and manufacturers. In either case, the effectiveness of kudzu as a treatment for alcoholism remains a matter of debate.

Studies aimed at defining the possible mechanism of action of kudzu in reducing alcohol consumption and withdrawal symptoms focus on the fact that the isoflavones derived from this plant, in particular daidzin, inhibit aldehyde dehydrogenase-2, an enzyme involved in the metabolism of ethanol and various other chemical substances.

Figure. Metabolism of alcohol

As shown, in humans alcohol is converted to acetaldehyde by the enzyme alcohol dehydrogenase, with the acetaldehyde then metabolized to acetic acid by aldehyde dehydrogenase. Many of the symptoms associated with a hangover, including headache and nausea, are due to the accumulation of acetaldehyde in the blood, which can be significant if a large amount of alcohol is consumed over a short period of time, or the enzyme aldehyde dehydrogenase is inhibited. Disulfuram, a drug used for the treatment for alcoholism, is an inhibitor of this enzyme. Because a patient taking disulfuram knows he will become quite ill if even a small amount of alcohol is consumed, he is motivated to resist the temptation to consume alcoholic beverages. In this way, disulfuram can be helpful in modifying the behavior of an alcoholic.

In 2000, daidzin was found to be a selective inhibitor of aldehyde dehydrogenase-2. As compared to other dehydrogenases in this family, aldehyde dehydrogenase-2 contributes in only a minor way to the metabolism of ethyl alcohol, although it is important in the metabolism of certain endogenous chemicals, such as serotonin, norepinephrine, and dopamine. This explains why administration of kudzu extracts or isoflavones at doses that reduce alcohol consumption, does not, like disufuram, a more nonselective inhibitor of this enzyme family, increase blood levels of acetaldehyde. As studies with chemical derivatives of daidzin indicate a correlation between inhibition of aldehyde dehydrogenase-2 and reduction in alcohol consumption, the two actions may be related. While there are suggestions that the kudzu isoflavones act in the brain to modify the response to alcohol, the current weight of evidence indicates that these isoflavones probably act outside the central nervous system to modify the production of endogenous agents, which in turn affect the absorption, distribution, or action of alcohol in such a way that its consumption is less rewarding. It is unknown whether this same action is responsible for the reported beneficial effect of kudzu in reducing the symptoms of alcohol withdrawal.

While it does not appear that the effect of kudzu constituents on alcohol consumption is mediated through a direct action on the brain, there are reports that phytoestrogens, such as daidzin and chemically related agents, influence cognition, have neuroprotective properties, and reduce anxiety.The extent to which these actions are due to a direct effect of the isoflavones or their metabolites on the brain is unknown.

Outside of possible central nervous system actions, puerarin, a potassium channel inhibitor, has been proposed as a treatment for cardiac arrhythmias. In addition, the kudzu isoflavones genistein and daidzein restore vascular function in spontaneously hypertensive rats, confirming the potentially beneficial cardiovascular actions of these compounds. A number of studies also demonstrate the anti-inflammatory effects of these isoflavones, in particular daidzein and genistein. This has led to the suggestion that these agents, and perhaps other isoflavones or their derivatives, may be useful for the treatment of asthma and rheumatoid arthritis. There are also suggestions that daidzin and genistein inhibit breast cancer cell motility and decrease the risk of lung cancer. Although some of the anti-inflammatory effects of these compounds, such as inhibition of NF-kappaB and tissue necrosis factor-α, could explain such effects, it remains to be seen whether these in vitro actions occur in humans at clinically appropriate doses.

Adverse Effects

Clinical and laboratory animal studies suggest that neither the use of kudzu root preparations nor any of the individual isoflavones studied thus far is associated with significant adverse effects. This is not surprising inasmuch as the isoflavones found in kudzu are common to the legume family and therefore widely consumed as food products. For example, soy beans are a major source of genistin in the diet.

Studies have suggested that consumption of kudzu isoflavones for as little as ten days modifies the activity of drug metabolizing enzymes and intestinal drug transporters. Other concerns, based on in vitro studies, include a possibly adverse effect on diabetics secondary to a daizdin-induced inhibition of glucose transport, and the accumulation of acetaldehyde or other substances in tissue as a result of the long-term inhibition of aldehyde dehydrogenase-2. Overall, the data accumulated to date suggest that kudzu and its isoflavones are safe for human consumption at the recommended doses.

Pharmacological Perspective

Kudzu root extract, and individual isoflavones contained therein, suppress excessive alcohol consumption in laboratory animals and may ameliorate alcohol withdrawal symptoms. While these effects have been noted for centuries, the human data are mostly anecdotal, with clinical trials yielding conflicting findings. Inasmuch as administration of kudzu has no obvious central nervous system consequences, it seems unlikely that an effect on alcohol consumption and withdrawal is due to an action on the brain. Rather, it appears the isoflavone constituents, and perhaps other chemicals in the plant product, modify enzymes responsible for the production of endogenous chemicals that can in turn influence the pharmacokinetics of alcohol or its central nervous system action. There is current interest in a possible role of inflammation in a variety of disorders, including depression, cardiac insufficiency, and cancer, in addition to the recognized role in arthritis. The anti-inflammatory and antioxidant actions of isoflavones include inhibition of NFkappaB, a cellular agent that initiates the inflammatory cascade. Both daizdin and puerarin have been shown to inhibit NFkappaB. Because kudzu and its constituent isoflavones appear safe, they would be superior to other drug-based approaches for treating alcoholism if further clinical studies show they are effective in this way.

Based on the data accumulated thus far, the value of kudzu as a neuroprotectant or anxiolytic is even more speculative than its possible utility as a treatment for alcoholism. This is because there is evidence indicating that the isoflavones may not penetrate into the brain, which is generally necessary for an agent to display neuroprotectant or anxiolytic activity. Also, because many of the kudzu constituents are rapidly and extensively metabolized in the intestine and liver, it may be difficult to identify the chemicals in the extract, or their metabolites, that may directly influence the brain. Until such substances have been characterized, and their accumulation and retention in the brain demonstrated, it would appear that any responses attributed to kudzu are due primarily to effects outside the central nervous system.

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