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Health Benefits and Clinical Impact of Red Yeast Rice

M. Kalaivani & R. Sabitha & V. Kalaiselvan & A. Rajasekaran 

Abstract

 

Chinese red yeast rice (RYR), a natural food obtained after fermenting rice with Monascus purpureus. RYR contains unsaturated fatty acids, sterols, B-complex vitamins and monacolins with antioxidant properties. Scientific evidences showed that fermented RYR proved to be effective for the management of cholesterol, diabetes, cardiovascular disease (CVD) and also for the prevention of cancer. This review article describe about the usage of RYR in human being.

 

Introduction

 

RYR is a Chinese traditional food produced by fermenting cooked rice kernels with yeast Monascus purpureus, which turns rice into reddish purple kernels due to its pigmenta- tion capability. The use of RYR in China dates back to first century AD. It has been used as preservative and coloring agent for fish and meat. RYR is also mentioned in ancient Chinese pharmacopeia of medicinal food and herbs states that it is being used as a medicine for digestion and revitalization (Heber et al. 1999a). Commercially red yeast rice is produced by solid state fermentation (Fig. 1) of rice with yeast Monascus purpureus that belongs to the family Aspergillaceae (Wang and Lin 2007). Monascus rice products are gaining importance as dietary supplement in United States and many Asian countries, due to its anti- cholesterol activity. RYR is produced by traditional fermentation contains chemical constituents that resemble HMG-CoA reductase inhibitors (statins). Statins are the class of hypolipidemic drugs capable of reducing choles- terol by inhibiting enzyme HMG-CoA reductase enzyme, a rate limiting enzyme of mevalonate pathway of cholesterol synthesis.

RYR contains nine major chemical constituents which are chemically resembled to statins (Heber et al. 1999a). Different types of monacolin have been studied from RYR, Where monacolin K was found to be identical to lovastatin (Hong et al. 2008). Lovastatin is also a class of HMG-CoA reductase inhibitors used for lowering of cholesterol levels. Lovastatin is also isolated from a fungi Aspergillus terreus (Bobek et al. 1998). The other constituents such as unsaturated fatty acid and sterols (Table 1) are reported to give synergistic effect for its hypolipidemic activity (Wang 1997; Moghadasian and Frohlich 1999). Meanwhile, flavonoids, phytosterols, and pyrrolonic compounds pos- sess potential to reduce blood sugar and triglycerides levels while raising HDL-C. It is also found to be useful in treatment of metabolic syndromes (Wang and Lin 2007). The present review is focused on the study of beneficial role and clinical effects of RYR on human health and the safety and efficacy of RYR in the usage of human being for the treatment and management of various diseases.


Isolation and Characterization of RYR

 

RYR contains numerous active constituents, namely mon- ascodilone and monocolin from Monascus purpureus. NMR analysis of RYR reported to possess a propenyl group on a pyrone ring, an aromatic ring, and a gamma- lactone group (Wild et al. 2002). There are 14 monacolin compounds identified such as monacolin K (mevinolin), J, L, M, X and their hydroxy acid form, such as dehydromo- nacolin K, dihydromonacolin L, compactin, 3α-hydroxy- 3,5-dihydromonacolin L, etc., were identified in RYR by HPLC (LI Yong-Guo et al. 2004). One of these, monacolin K, is a potent inhibitor of HMG-CoA reductase inhibitor, which is also known as mevinolin or lovastatin, a semi-synthetic derivative now in use as cholesterol-lowering drugs.

Recently two new compounds, such as monasfluore A and monasfluore B have been isolated and the structures were elucidated by electrospray ionization mass spectrom- etry, which contains an alkyl side chain, gamma-lactone, and propenyl group (Huang et al. 2008). Other compounds include sterols (β-sitosterol, campesterol, stigmasterol, sapogenin), isoflavones and monounsaturated fatty acids.

 

Effect in Cholesterol Management

 

Scientific evidences showed that RYR contains HMG-CoA reductase inhibitors, which inhibits the cholesterol synthesis in liver, which may be Monocolin I to IV (Heber et al. 1999a). Pharmacological investigations also proved that Monascus fermentate reduces experimentally induced hy- perlipidemia in animal models (Endo and Monacolin 1980).

Increase in cholesterol level is the risk factor for atherosclerosis, can be managed by statins but it induces liver function abnormalities. In an experimental study conducted by Man et al. (2002) to determine the cellular effect of RYR on cholesterol synthesis in human hepatic cells (HepG2), it was found that RYR had a direct inhibitory effect on HMG-CoA reductase activity (7869% of control) and cholesterol levels in HepG2 cells treated with RYR (25100μg/mL) were also significantly reduced in a dose-dependent manner (8145% of control, respectively).

RYR also contains unsaturated fatty acids that may also contribute in reducing the serum cholesterol level (Wang et al. 1997) by lowering triglycerides (Wang et al. 1997; Qin et al. 1998). It also contains sterols, interferes cholesterol absorption in liver (Moghadasian and Frohlich 1999). The combination of dietary sterol with statin will give effective anti-cholesterol activity (Plat and Mensink 2001). RYR is a natural food supplement which contains both sterols and statins (Bibhu Prasad Panda et al. 2008). RYR also contains fiber, trace elements, unsaturated fatty acids (Ma et al. 2000) and B-Complex vitamins (Palo et al. 1960). RYR also suppresses the adipogenesis (Jeon et al. 2004). RYR extracts also found to regulate adipogenic transcription factor and gene expression in 3T3-L1 cells. In a study by Jeon et al. (2004), RYR decreases glycerol-3-phosphate dehydrogenase activity and lipid accumulation, a marker of adipogenesis. The key adipogenic transcription factors were also decreased by RYR extract (Jeon et al. 2004). Effect of Chinese red yeast rice on long term consumption was also studied by Wei et al. (2003). They studied the effects of red yeast rice on serum lipids and severity of atherosclerosis in high cholesterol fed rabbits for 200 days and found that serum total cholesterol level reduced 25% and 40% respectively in rabbits treated with 0.4 or 1.35 g/kg/day of RYR on comparison with controls. This treatment lowered serum LDL-cholesterol. This 200-day treatment significant- ly reduces serum triglycerides and atherosclerotic index (ratio of non-HDL-cholesterol to HDL-cholesterol). The sudanophilic area of involvement was 80.6% in controls and reduced significantly to 30.1% on the low dose and 17.2% on the high dose of RYR. Lovastatin also reduces severity of lesions by 89% (sudanophilia) and 84% (visual; Wei et al. 2003).

Various clinical investigations on animal studies also proved the hypolipidemic activity of Chinese red yeast rice, the summary of the clinical evidence are given in Table 2. Meta-analysis of clinical trials on efficacy of RYR on hyperlipidemia showed significant reduction of serum total cholesterol levels (mean difference 0.91 mmol/L) trigly- cerides level (0.41 mmol/L) LDL-cholesterol level (0.73 mmol/L) and increase of HDL-cholesterol level (Liu et al. 2006).

 

Role of RYR in CVD

 

The inhibition of cholesterol synthesis is effective for primary and secondary prevention of heart diseases (Li et al. 2005). Patients with hypercholesterolemia and cardiovascular risk can be treated better with cholestin, a RYR supplement (Gavagan 2002). Hyperhomocysteine- mia is associated with dysfunction and risk factor of cardiovascular diseases.

Lin et al. (2008) investigated the effect of cholestin extract on the expression of vascular cell-adhesion molecule-1 (VCAM-1) by homocysteine (HCY) treated human aortic endothelial cells. The experiment showed that RYR extract significantly suppresses the cellular binding of human monocytic cells to HCY stimulated endothelial adhesion. From the experimental results, authors concluded that RYR extract effectively reduces HCY stimulated endothelial adhesion property as well as down regulates intercellular reactive oxygen species formation, NF-kappa B activation and VCAM-I in human aortic endothelial cells, supports the fact that expressions of dietary supplements with RYR will be effective in treatment of arthrosclerosis diseases. Table 3 summarizes the clinical evidences for the use of RYR in cardiovascular disease management.

  

Effect of RYR in the Treatment of Cancer

 

RYR reduces blood cholesterol levels in rabbits on atherogenic diet (Wei et al. 2003; Lee et al., 2006) and can reduce lipid accumulation in 3T3 L1 preadipocytes (Jeon et al. 2004). In a randomized prospective controlled trial, RYR, in comparison to a placebo, decreased total cholesterol, triglycerides, and apolipoprotein B in hyper- cholesterolemic individuals (Lin et al. 2005). Cholestero- genesis is a key factor for tumor growth and HMG-CoA reductase activities are up-regulated in colon tumors (Buchwald 1992; Hentosh et al. 2001; Notarnicola et al. 2004; Caruso et al. 2002). The pharmacological evidences showed that statins may inhibit colon cancer cell growth and thereby reduces incidence of colon cancer (Agarwal et al. 2002; Ukomadu and Dutta 2003; Lin et al. 2006). In a population-based study, statin consumption was associated with 47% reduced risk of colon cancer (Poynter et al. 2005). Mee Young Hong et al. (2008) reported the anticancer effect of RYR on colon cancer cells and the anticancer effect was more in pigment rich fraction of RYR that showed anti-proliferation and pro-apoptotic activities (Martinkova et al. 1999; Heber et al. 2001). But the authors feel that further studies have to be performed to establish anticancer and apoptosis effect of active constituents of RYR.

Monascus pigments comprises of monascin, ankaflavin, monascorubrin, rubropunctatin, monascorubramin, and rubropunctamin (Chen et al. 1971; Manchand et al. 1973; Kuromo et al. 1963; Hadfield et al. 1967; Fowell et al. 1956; Kim et al. 2006; Journoud and Jones 2004). Monascorubrin pigment reported to possess antimicrobial activity and inhibits the spread of skin cancer in mice (Yasukawa et al. 1994, 1996)

 

Effect in the Management of Diabetes

 

A part from anti-cholesterol and anticancer activity, RYR shows glucose lowering effect in streptozotocin (STZ)- induced diabetic rats (Chang et al. 2006). RYR is red yeast rice fermented with Monascus pilous and Monascus purpureus. Single oral administration of RYR decreased plasma glucose in STZ-diabetic rats in a dose-dependent manner from 50 to 350 mg/kg. It reduces the elevation of plasma glucose induced by an intravenous glucose chal- lenge test in normal rats. The results showed the reversion of mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) in liver from STZ-diabetic rats in a dose- dependent manner by the repeated oral treatment of RYR three times daily for 2 weeks. The authors concluded that oral administration of RYR could decrease hepatic gluco- neogenesis to lower plasma glucose in diabetic rats lacking insulin.

Chang-Chih Chen and I-Min L (2006) reported dose- dependent reduction in plasma glucose and increase in plasma insulin level/C-peptide. They also reported that increase of plasma level of insulin or C-peptide was inhibited by 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP), but not affected by the ganglionic nicotinic antagonist, pentolinium or hexamethonium, indicating the action through muscarinic M3 receptors. Authors also found that RYR inhibited the activity of hemicholinium-3 and vesamicol (an inhibitor of choline uptake and vesicular acetylcholine transport respectively). From the above-said experimental results authors concluded that RYR has the ability to increase the release of ACh from the nerve terminals, which in turn stimulates muscarinic M3 receptors in pancreatic cells and augment the insulin release to result in plasma glucose lowering action.

 

Effect of RYR on Osteoporosis

 

Nutritional therapy plays a vital role in the treatment of osteoporosis. A bone morphogenetic protein regulates the osteogenic differentiation during bone fracture repair. In the recent study, it was found that RYR extract increases the osteogenic activity, cell viability, and mitochondrial activity (Ricky and Bakr 2008). The study suggested that the effect of bone formation is due to the inhibition of HMG-CoA reductase in the mevalonate pathway may increase bone cells formation. The effect of red yeast rice on new bone formation might be specific because no increased total protein was detected (Ricky and Bakr 2008). Further studies are required to confirm whether statin like com- pounds possess osteogenic activity or not.

 

 

Other Benefits of RYR

 

RYR in amelioration of impairment of memory and learning ability in intra cerebro-ventricular amyloid beta- infused rat by repressing amyloid beta accumulation was also proved by Lee et al. (2007c). Apart from pharmaco- logical activities it is been used as preservative due to Monascidin A (Wong and Bau 1977; Wong and Koehler 1981; Bau 1977) against Bacillus, Streptococcus, and Pseudomonas. RYR is used as additive in various dietary formulations due to its preservation and coloring property.

 

 

Drawbacks of RYR

 

The only drawback of RYR is citrinin; a mycotoxin produced along with monocolins (Lee et al. 2007a, b) in same pathway which cause neurotoxicity in long term consumption of RYR. Venkateshwar et al. (2008) also observed RYR induced myopathy in a patient on routine RYR consumption in the treatment of elevated triglycer- ides. The patient developed same type of myopathy when treated with statin. Other few case reports of myopathy with RYR were also reported. One report described a 28-Year- old female with a renal transplant developed rhabdomyol- ysis on consumption of RYR (Prasad et al. 2002; Smith and Olive 2003; Mueller 2006).

 

Interactions

 

RYR, a cholesterol-lowering compound (statin) medica- tions found to enhance their effect and increases the risk of liver damage. Grapefruit reported to enhance the effects of statins and its concentration in blood, increases the risk of side effects and liver damage (Kane and Lipsky 2000). RYR acts similarly to statins in the body therefore grapefruit should be avoided while taking RYR. Statins may deplete the coenzyme (Vercelli et al. 2006) called CoQ10 from the body (Kane and Lipsky 2000). CoQ10 is very important in heart and muscle health and in energy produc- tion. Side effects of CoQ10 depletion include fatigue, muscle aches, pains, and damage. It is also advised to supplement our diet with CoQ10, 150200 mg at night, while taking RYR products, and for 4 weeks after you stop taking RYR.

 

Conclusions

 

RYR reflects the thin line of deference between drug and a food. Although RYR was not approved by FDA, it possesses excellent anti-cholesterol activity similar to statin drugs, and with comparable low incidence of adverse effects. Apart from anti-cholesterol activity its role in the prevention of CVD, cancer, management of diabetes, osteoporosis were also proved. Therefore, extensive re- search should be carried out to explore its active constit- uents and their pharmacological activity. Only a limited amount of bioavailability profile and clinical data exists to support their efficacy hence to be carried out to conclude its effect in human beings and their possible side effects.

 

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Qin, S., Zha

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