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Red yeast rice is also known as "Hong qu" in Chinese. It has been used as a traditional Chinese cuisine, medicine and food colorant for over 1000 years. Such products are produced by fermentation of steamed rice with food fungus Monascus spp.; the final product then gives a natural red color to rice hence it is referred as red yeast rice . In many other Asian countries including Japan, Korean, Thailand and Philippines, red yeast rice is also used as a food preservative and natural food colorant. The origin of red yeast rice can trace back to Song Dynasty of China (sixteenth century). As recorded in the literature from Song Dynasty, red yeast rice has been used as a food colorant for meat, fish and bamboo shoots . Later in the Ming Dynasty, scientist Song, Yingxing describes the functionality of red yeast rice in "Tian Gong Kai Wu". In this book, detailed description is documented of how red yeast rice can extend shelf-life of fish and meat, therefore, prevent them from becoming rancid in summer time or heat weather .
In general, red color is symbolized as a propitious sign in China; using red yeast rice as the red pigment for food stuff coloration is very popular national wide. In south China, provinces including Fujian, Zhejiang and Jiangxi are becoming the major areas of red yeast rice production. One of the most famous dishes in Chinese cuisines from local area is called "Hong Cao", which served red yeast rice with stir-fry, steam or roast meat such as "Hong Cao Pork," "Hong Cao Chicken," "Hong Cao Fish,". Another traditional meat product commonly served with red yeast rice is Chinese style sausage.
In addition to its uses in meat cuisine and meat products, red yeast rice has been used in fermentation industry for red soy bean curd production. Red soy bean curd is a popular cheese-like product that served as a spice. Red yeast rice can also serve as "Jiu Qu" which directly translates as wine starter culture. Red yeast rice is used by Chinese brewer to produce red rice wine. The red rice wine is called "Hong Qu Jiu" in Chinese. Such product has a golden color, mellow aroma, elegant flavor, and pleasant aftertaste.
In ancient China, as old custom, red yeast rice has been used to cure diseases. Red yeast rice is considered as a natural folk medicine. Literature describes it as "sweet in flavor and warm in property" with therapeutic and beneficial effect on digestion, circulation and cardiovascular system, such effect has been stated by Shi-zhen Li in "Ben Cao Gang Mu" [4, 5]. For women who just gave birth, it suggested that consuming red yeast rice or red rice wine will enhance blood circulation and help menstrual irregularities . Furthermore, there exist records suggested red yeast rice provides positive influence on spleen hence balance the "yin" and "yang" in the human body .
Since 1979, Dr. Endo first isolated monacolin K from Monascus species and identified its hypocholesterolemic effect , red yeast rice then attracted considerable attention. The primary and secondary metabolites of red yeast rice have been studied during the past decades. Evidence from both animal and human studies suggests that the beneficial attributes of red yeast rice are most from its secondary metabolites. Hence present paper provides a brief review of red yeast rice secondary metabolites (Table 1) and its therapeutic effects as a functional food.
Traditional Production Methods
After the Ming dynasty, the method of red yeast rice production was improved. Detailed processing description of red yeast rice production has been documented in "Ben Cao Gang Mu" (AD 1590). Solid-state fermentation technology has been used to produce red yeast rice since then. The method of making red yeast rice is based on fermentation process on a bed of cooked rice. Production of red yeast rice requires starter culture also known "the seed". The seed is composed by a mass of mold spores grown on a suitable carbohydrate base such as rice or wheat. The seed for red yeast rice production is, therefore, spores of mold Monascus spp. . Before fermentation starts, raw material selection is also critical. Nonglutinous rice is the best choice for raw ingredient due to its high starch content and low stickiness . The glutinous varieties tend to stick together thus cause poor heat dissipation hence result in reducing the survival rate of starter culture. Figure 1 presents the flow chart of traditional red yeast rice production .
Figure 1: Processing steps of red yeast rice production.
White rice (Raw material)
Cleaning and Soaking (about 1 day or more)
Drained dry till moist
Steaming and cooling
Inoculation and incubation
In pool heat preservation
Raw material is cleaned and soaked for about one day or more and then drained. The moist rice is cooked and mixed with diluted vinegar; such a slightly acidic environment is optimal for the Monascus growth (because of Monascus spp. are acidophilic). Cooked rice is then inoculated. The inoculated rice is mixed thoroughly and then incubated at temperature 33 - 42oC. During fermentation, water should be added occasionally. At different growth stages, water requirement varies; especially, during the peak growth period, the replenishment of water is critical. During the first few days of fermentation, rice kernel showed pink color then has been stirred and shaken to redistribute the moisture. The kernels should be spread out and piled up and turned in order to provide sufficient aeration hence increase the fermenting mass [4, 10]. Within about 2 weeks, the rice is then expected to turn to a deep red color.
Traditionally red yeast rice is produced by solid-state fermentation, which includes inoculating starter culture on cooked rice. The advantages of traditional method are low cost, good feasibility, easy to manage and less waste. It is simple to recycle most of the metabolites. The contemporary method of red yeast rice production is still by the traditional solid-state fermentation on cooked rice .
Bioactive Metabolites of Red Yeast Rice
Red yeast rice contains various secondary metabolites. Many of these are synthesized from the polyketide pathway in Monascus spp. . Some of them are identified, including monacolins (Figure 2), gamma-aminobutyric acid (GABA) (Figure 3) and several pigments from Monascus (Figure 4). Their bioactive functions have been studied extensively during the past decades, especially cholesterol modulation effect of monacolins and hypotensive effect of GABA . In the following paragraph, effect of secondary metabolites of red yeast rice on health will be introduced.
Hypercholesterolemia and hyperlipidemia are two conditions that can be secondary to many diseases and tightly related to cardiovascular disease . Hypercholesterolemia, especially, elevated plasma low-density lipoprotein cholesterol (LDL-C) in plasma is considered in connection with atherosclerosis, stroke and other related diseases . Current therapeutic methodology is to block the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase . HMG-CoA reductase is the rate limiting enzyme of the cholesterol biosynthetic pathway . It is also a key to the biosynthesis of cholesterol, as it is expected that blocking the synthesis of cholesterol then result in lower cholesterol levels in plasma. Brown and Goldstein demonstrated that inhibition of HMG-CoA reductase may upregulate the expression of LDL-C receptors (ApoB/Apo E receptor); hence increase the uptake of LDL-C through the receptor mediated pathway which therefore leads to a reduction of LCL-C in plasma [15, 16]. The inhibiting HMG-CoA reductase activity of red yeast rice comes from a family of naturally occurring substances called monacolins . Dr. Endo initially isolated monacolins from Monascus app. and then identified its structurally identical to lovastatin [7, 18]. Monacolins are well known as its pharmacological effect as a hypocholesterolemic agent. Among the monacolins (monacolin K, monacolin J, monacolin M, monacolin X, monacolin L), monacolin K is considered as the most efficacious compound which represents about half of total monacolin yield in red yeast rice . In animal and human studies, monacolin K exerts cholesterol lowering effect in plasma.
Evidence for Health benefits of Monacolins
Wei et al. demonstrated LDL-C lowering effect of red yeast rice by feeding rabbits red yeast rice enriched diet over 200 days. The rabbits were randomized to control diet, atherogenic diet, atherogenic diet enriched with either lower dose or higher dose of red yeast rice or with lovastatin. After 200 days diet intervention, it is evident that serum total cholesterol of rabbits on lower and higher doses of red yeast rice was reduced by 25% and 43% respectively in comparison with animal fed atherogenic diet (p<0.05). Serum LDL-C was also reduced by 7% and 24% in animal fed red yeast rice enriched diet (p<0.05) . In addition, triglyceride was also reduced by red yeast rice consumption. Xuezhikang is an extract of cholestin which has served as a red yeast rice dietary supplement in China. Study conducted by Wu et al. evaluated effects of "Xuezhikang" (commercial product 1.2g/day contained 13.5mg total monacolins, WBL Peking University Biotech Co., Ltd., China) on plasma cholesterol and endothelial cells function in rabbits fed cholesterol enriched diet. After a 12-week diet intervention, Xuezhikang favorably modulated rabbits' lipid profile. Serum total cholesterol, LDL-C and triglyceride levels were all reduced in Xuezhikang treated group as compared to animals in control group (p<0.05) . Similar results were also observed in hypercholesterolemia hamster when they were fed Monascus powder at dose 10.78mg/100 g body weight/day. Hamsters were offered to such experimental diets for 4 weeks and 8 weeks, respectively. In the results, oral administration indeed proven Monascus powder reduced total cholesterol in plasma by 31.2% and 22.0% at week 4 and week 8, respectively (p<0.05). LDL-C and triglyceride levels were also reduced by Monascus powder consumption in hamster . Lin et al. also evaluated effects of monacolin K-containing red yeast rice product (Unchole 1.0g/day containing 8.0mg total monacolins, Taiwan Tobacco & Liquor Corp.) in a hamster model. Results suggested that after 31 days, animals in "Unchole" treatment group had significant lower total cholesterol, LDL-C and triglyceride levels in serum compared with animals in control group fed hypercholesterolemia diet .
Data from human clinical trials also suggest beneficial effects of red yeast rice products on lipid profile and cardiac health. Heber et al. demonstrated that by offering 2.4g/day cholestin (red yeast rice product contained about 9.6mg total monacolins) to 83 otherwise healthy subjects with hyperlipidemia for 8 and 12 weeks, total cholesterol, LDL-C and triglycerides were significantly reduced in comparison with baseline data . Liu et al. examined effect of Xuezhikang on lipid profile and inflammatory markers in coronary heart disease (CHD) patients. Data indicated that after 6 weeks consumption of 600mg Xuezhikang (300 cholestin per capsule) per day, the fasting total cholesterol, LDL-C and triglyceride reduced by 21%, 30% and 25%, respectively in CHD patients (p<0.05) . Similar results were also reported by Zhao et al, in 2004. By offering 12g/day Xuezhikang to CHD patients for 6 weeks, end point measurement of total cholesterol, LDL-cholesterol, triglyceride levels were reduced by 18.8%, 28.3% and 31.1%, respectively (p<0.001). HDL-cholesterol was increased by 17.4% (p<0.001). In addition, patient with Xuezhikang treatment had significant reduced fasting high-sensitivity C-reactive protein (p<0.001), as well as significant improved preprandial and postprandial flow-mediated vasodilatation (p<0.001) .
Other than its positive influence in blood lipids, effect of Xuezhikang on cardiac protection has also been investigated. A large scale clinical trial "China coronary secondary prevention study" was conducted in 66 centers across China from May 1996 to December 2003 to evaluate whether such red yeast rice extract products can reduce the risk of cardiac events and total mortality in Chinese CHD patients. Total 4870 CHD patients were randomized into either a treatment group (Xuezhikang capsule 0.6g, two capsules per day) or placebo group. After four years follow up, incidence of nonfatal myocardial infarction was reduced by 60.8% (p<0.0000), incidence of death from CHD was reduced by 31.0% (p<0.0048). Total mortality was lower by 33.0% (p=0.0003).
Even though red yeast rice and related products shown promising results in many studies, safety is still an issue since adverse effects have been reported after supplementing during several human trials (reviewed in ). In addition, citrinin levels in red yeast rice products exist as another safety concern. Citrinin is produced during fermentation of red yeast rice and found to be a hepatotoxic and nephrotoxic ingredient in red yeast rice and related products . Citrinin has negative effect in liver function. Strain screening and submerge cultivation can manage citrinin level during fermentation process. However, production of monacolin K without existence of citrinin is not possible yet .
Red yeast rice fermented by Monascus also has an effective action on lowering blood pressure. Component in red yeast rice responsible for such effect is known as gamma-aminobutyric acid (GABA). In addition to its hypotensive effect, GABA also possesses effects on brain tissue bloodstream mobilization and neurotransmitting . GABA is produced by decarboxylation of glutamic acid by glutamate decarboxylase . Glutamic acid is produced during the fermentation process of streamed rice by two enzymes (an acid protease and an acid carboxypeptidase); such two enzymes are secreted and accompanied by the growth of starter mold . The amount of GABA produced during fermentation is strain-dependent . Studies done by Su, et al. suggested solid state cultivation have relatively high yield of GABA compared to submerged cultivation .
Evidence for Health Benefits of GABA
It has been known that intravenously or orally administered GABA significantly lowers the blood pressure in animals and humans. Wu, et al. showed that after 8 weeks of oral administration of red yeast rice at dose of 150mg/kg, systolic blood pressure and diastolic blood pressure in spontaneous hypertensive rats were significantly reduced compared with animal on control diet (p<0.05). Data also suggested that red yeast rice consumption prevens genetically increased blood pressure . Work done by Rhyu, et al. indicated that an aqueous extract of red yeast rice fermented with Monascus ruber induced aortic relaxation in rats by increasing the release of NO from endothelium. Hsieh and Tai demonstrated that treatment with 1mg/kg/day GABA containing aqueous extract from Monascus purpureus M 9011 can prevent fructose induced hypertension in a rat model; such effect did not observe on blood pressure in normotensive rats fed regular diets. In addition, Hsieh and Tai tested the reverse effect of treatment; results suggested that GABA containing aqueous extract from M 9011 can reverse the elevated blood pressure to a normal level, after fructose-induced hypertension is established . However, in the same study, data also indicated that pure GABA at the same dose as that contained in M9011 failed to provide same hypotensive effect, which suggested that besides GABA, other components in M9011 may responsible for its hypotensive impact in rats. Kushiro et al. evaluated beni-koji (red yeast rice product) effect on patients with mild hypertension. In this study, patients in treatment group received beni-koji aqueous extracts containing juice on daily base (27 g beni-koji/day); patients in control group received blank juice as placebo. The experimental period was 8 weeks. Casual blood pressure and 24-hr non invasive ambulatory blood pressure (ABP) were measured. Patients in treatment group presented with significant lowered casual systolic and diastolic pressure compared with control group patients (p<0.05). Reduced ABP was also observed in treatment group patients (p<0.05). Safety evaluation was also performed in their study. Data suggested that beni-koji can be considered as an effective and safe food material for mild essential hypertension .
Pigments from Monascus
Six well-known Monascus pigments (azaphilones) exist. These pigments can be divided into three pairs. The red colorants named rubropunctamin and monascorubramine. The orange colorants are rubropunctatin and monascorubrin. The yellowish colorants are monascin and ankaflavin . Monascus pigments are stable in the pH range of 2-10, and heat stable . Monascus pigments are often applied in oriental food stuff, especially in Southern China, Japan and Southeastern Asia. In Japan, from 1981 to the end of nineties, consumption of Monascus pigments increased from 100 to 600 tonnes per year, which was valued at $ 1.5 million . In Japanese market, the major application of Monascus pigments is coloration for food products that high in protein content, such as processed meat (sausage, ham), marine products (fish cake) and surimi [10, 35].
Other than its coloration property, pigments extract from Monascus suggested carcinogenesis inhibitory effect in several rodent models. Yasukawa et al. proposed that monascorubrin inhibited tumor promotion due to its anti-inflammatory activity in mice with skin tumor with chemical inducement . Later, Akihisa et al. demonstrated that oral administration of monascin produced an anti-tumor-initiating effect on chemical induced skin cancer in mice . The same group conducted another study evaluating 10 components extracted from Monascus which included six pigments (monascin, ankaflavin, rubropunctatin, monascorburin, rubropunctamine, and monascorburamine) investigating their anti-tumor-initiating effect on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation mice. Results were in good accordance with their previous observations. Among the compounds tested, all six pigments exhibited inhibition on TPA-induced inflammation in mice. The author concluded that all six Monascus extracted pigments (azaphilone) are valuable as an antitumor agent in chemical carcinogenesis . The orange pigments, rubropunctatin and monascorubrin have shown antibiotic effect on inhibiting bacteria growth . Although toxicity studies show that Monascus pigments are safe for consumption, the application of Monascus pigments is limited because of its low water solubility and light sensitivity. Many investigations have focused on such limitations. Monascus pigments produced by advanced technologies showed high water solubility and less light sensitivity [40, 41].
Red yeast rice is traditional food stuff produced by fermenting cooked rice with the food fungus Monascus spp. Red yeast rice is widely used in Asian countries as a natural food colorant for local cuisines. Natural components from red yeast rice such as monacolin K and GABA exhibit therapeutic effects in humans including hypocholesterolemia, hypolipidemia and anti-hypertension activity. Red yeast rice and related products also promote positive influence on cardiac health. The production of red yeast rice and related products, such as pigments extract from Monascus also provides great economic value in food colorant industry. Moreover, certain pigments suggest positive influences on inhibition of tumor initiation. Although red yeast rice and related product are well accepted as a dietary supplement, its citrinin content and complexity of components are still concerns.