Red Yeast Rice

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Scientific Name(s): Monascus purpureus Went. Family: Aspergillaceae

Common Name(s): Monascus , Zhitai , Xuezhikang (China), koji, , ang-khak , beni-koji , red-koji (Japan), rotschimmelreis (Europe), Hon-Chi (Mandarin), red yeast , red mold , red rice yeast , Cholestin (USA). 1 , 2

Uses

M. purpureus is a natural source of mevinolin, the active ingredient of lovastatin, and therefore has beneficial effects in the treatment of hyperlipidemia. However, it should not be used in place of lovastatin and regular medical care because there are no studies that directly compare red yeast rice to a statin. Some evidence also exists for its antibacterial and anticancer effects, as well as its activity on glycemic metabolism.

Dosing

Red yeast rice is available commercially, primarily as a 600 mg capsule. Most manufacturers suggest a dosage of 2 capsules twice a day by mouth for a total of 2,400 mg/day. Commercial OTC products often contain coenzyme Q 10 to supplement the low levels of this enzyme found in patients with statin myopathy. Past clinical trials have used dosages of 2,400 mg/day.

Contraindications

Hypersensitivity to any components of red yeast rice. Anaphylactic reactions in certain patient populations are documented. Red yeast rice depletes tissue of coenzyme Q 10 , which may increase the risk of statin-induced myopathy. Therefore patients with muscle damage caused by statins should avoid use of red yeast rice.

Pregnancy/Lactation

Avoid use during pregnancy and lactation. The major ingredient in red yeast rice is monacolin K, which is also known as mevinolin or lovastatin and has statin-like activity. Statins are potential teratogens based on theoretical considerations and in small case studies. CNS and limb defects have been reported in newborns exposed to statins in utero.

Interactions

Avoid using red yeast rice with cholesterol-lowering (statin) medications, cyclosporine, or grapefruit juice due to additive effects, which can increase risk of liver damage and rhabdomyolysis.

Adverse Reactions

Meta-analysis of the efficacy of 3 red yeast rice preparations ( Cholestin , Xuezhikang , and Zhibituo ) from 93 randomized trials (9,625 patients) documented no serious adverse reactions. The most common adverse reactions included dizziness, decreased appetite, nausea, stomachache, abdominal distension, and diarrhea. A small number of patients suffered from increased serum blood urea nitrogen (BUN) and alanine aminotransferase (ALT) levels.

Toxicology

The nephrotoxic mycotoxin citrinin has been isolated from some strains of M. purpureus and Monascus ruber . No severe toxicities at high doses have been reported. Not recommended for use in patients with liver disease.

History

The use of red yeast rice dates back to the ancient Chinese pharmacopeia, Pen Chow Kang Mu , published during the Ming Dynasty in the 14th and 17th centuries. 3 The red mold species, M. purpureus , may be cultivated on starch-containing substrates. 1 The food and medicinal value of the species dates back prior to its recorded use in 800 AD. 4 In 1884, Dutch scientists studied the fungus Monascus after discovering its use by villagers in the colonial island of Java. Red yeast rice is derived from rice allowed to ferment with the yeast M. purpureus . In 1895, the M. purpureus species was isolated from red koji, named for the purple color of the culture. 2 , 5

Red yeast rice has been used in Chinese medicine to strengthen the spleen, promote or improve digestion, eliminate dampness and phlegm, promote or improve blood circulation, and remove blood stasis. During the Ming Dynasty, red yeast rice was described as “sweet in flavor and warm in property.” 6 , 7 The genus Monascus has been used for centuries in Asia as a source of pigment for coloring traditional foods. The medicinal properties of red yeast rice are valued throughout Asia, and the species is also used to make rice wine and as a food preservative for maintaining the color and taste of fish and meat. 6 Commercial food applications include coloration of sausage, hams, surimi, and tomato ketchup. The pigment has a long history of use as a food ingredient for Asian consumers, but not in Europe or America. However, a recent study documents the registration of numerous patents obtaining the use of Monascus as a food pigment in Japan, the United States, France, and Germany. 8

Chemistry

Red yeast rice forms naturally-occurring hydroxymethylglutaryl-CoA reductase (HMG-CoA) inhibitors, 9 a family of natural substances known as monacolins. The major ingredient in red yeast rice is monacolin K, which is also known as mevinolin or lovastatin. Monacolin K is also part of some, but not all, commercial red yeast-related products. 7 One chemical study using high-performance liquid chromatography with photodiode array detection documented a total of 14 monacolin compounds, including monacolin K, J, L, M, and X with their corresponding hydroxyl acid forms, as well as dehydromonacolin K, dihydromonacolin L, compactin, and 3-hydroxy-3,5-dihydromonacolin L. Starch is the most abundant ingredient, accounting for 73% of the bulk, while crude protein accounts for 15%. 7 Trace elements, magnesium and sodium, are the most abundant metal elements. The total monacolin content is usually 0.4% weight/weight rice. 7 Red yeast rice also contains sterols, such as beta-sitosterol and campesterol, that may block cholesterol absorption in the intestines. Unsaturated fatty acids, such as oleic, linoleic, and linolenic acids, and B complex vitamins, such as niacin, have been isolated and may further help reduce cholesterol. 1

Monascus produces several secondary metabolites, such as pigments, monacolins, gamma-aminobutyric acid (GABA), and dimerumic acid. 6 , 7 , 8 , 9 , 10 A total of 6 well-known natural pigments called azaphilones are produced by Monascus and include yellow (monascin and ankaflavin), orange (monascorubrin and rubropunctatin), and reddish purple (monascorubramine and rubropunctamine); each may have biological activity. 8 , 11 , 12 Commerical utilization of agro-industrial residues for pigment and enzyme production from M. purpureus is documented. 8 , 13 The natural pigment of Monascus also improves the organoleptic characteristics of various cheeses. 14

Monascidin A, another constituent of Monascus , has been characterized as citrinin by qualitative methods, mass spectra, and nuclear magnetic resonance. 15 Citrinin is a myotoxin especially toxic to liver and kidney tissue and is suspected of being a renal carcinogen leading to renal tumors. 16 Monacolin K and citrinin are polyketide derivatives and, thus, are produced at the same time. Chemical methods are available to remove citrinin and retain monacolin K in red yeast rice. 16

Uses and Pharmacology

Most research focuses on M. purpureus as a natural source of lovastatin and, therefore, has beneficial effects in the treatment of hyperlipidemia. However, evidence also exists for its antibacterial and anticancer effects, as well as its activity on glycemic metabolism. 17

Antibacterial activity

The activity of Monascus derivatives depends on the hydrophobicity of pigment derivatives and on the amount of pigment absorbed to the cell surface. 11

In vitro data

Antibacterial activity was found against gram-positive and gram-negative species. 1 , 18 , 19 Orange monascus pigments have been reported to have weak antibacterial activity, while the red pigment has little to no activity. 11 Orange pigments had antimicrobial activities against Bacillus subtilis , Escherichia coli , some filamentous fungi, and yeasts. 18 Monascidin A inhibited bacteria from the genera Bacillus , Streptococcus , and Pseudomonas . Two yellow pigments had bacteriostatic activity against Bacillus subtilis and inhibitory activity against Staphylococcus aureus . 1

Cancer

The mechanism of action may involve monacolin K and red yeast pigment fraction inhibiting de novo cholesterogenesis that is required for tumor growth. 5 Monacolin K is an effective anticancer agent that blocks the mevalonate biosynthesis pathway, inducing suppression of cancer growth. 20

In vitro data

Red yeast rice inhibited proliferation and stimulated apoptosis perhaps through caspases 4 , 8 , 9 and poly (ADP-ribose) polymerase cleavage in human colon adenocarcinoma cell lines. 5 Proteomic studies found monacolin K to inhibit cell proliferation through multiple protein expressions (a total of 20 proteins), including peroxiredoxins, cytoskeleton proteins, chaperone proteins, and energy-producing enzymes. Monacolin K may also alter the expression of some redox-related enzymes. 20 , 21 Three active components of Monascus fermented red yeast rice (monacolin K, monascorubrin, and ankaflavin) have documented antiproliferative effects against tumor cells. 20

Animal data

Oral administration or topical application of monascorubrin pigment inhibited skin cancer development in mice. 5 , 22 , 23

Diabetes

The postulated mechanism of action involves the release of acetylcholine from nerve terminals, which in turn stimulates muscarinic receptors in pancreatic cells, increasing insulin release and resulting in lower plasma glucose. 24

Animal data

Hon-Chi (red yeast rice fermented with Monascus pilous and M. purpureus ) decreased plasma glucose in a dose-dependent manner in rats. 24 An increase in plasma insulin or C-peptide was also observed and similar results were documented in streptozotocin-induced diabetic rats. 25 Another study found that Hon-Chi improved insulin sensitivity in rats and delayed development of insulin resistance. 2

Hyperlipidemia

Monacolin K competitively inhibits HMG-CoA reductase, the enzyme that catalyzes HMG-CoA to mevalonate and then to cholesterol, which results in decreased very low density Lipoprotein and plasma triglycerides, as well as low density Lipoprotein.

Animal data

In the late 1970s, it was discovered that Monascus metabolites inhibited HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis. 26 Zhitai (0.25% HMG-CoA reductase inhibitors) and Xuezhikang (the ethanolic extract containing 1.1% HMG-CoA reductase inhibitors) have both been extensively studied in China. Monascus is in both of these. 27 In 3 separate animal studies, Xuezhikang was effective in reducing serum cholesterol levels, similar to lovastatin. Xuezhikang was also found to suppress aortic atherosclerotic plaque formation and lipid accumulation in the animal livers. The dose of 0.4 and 0.8 g/kg in 1 report reduced serum cholesterol levels by 44% and 59%, respectively. 28

Clinical data

Many Chinese studies evaluating Monascus are available. One major randomized, multicenter trial involved 446 hyperlipidemic patients with cholesterol levels greater than 230 mg/dL. At the end of an 8-week treatment, total serum cholesterol was reduced an average of 23%, triglycerides were reduced by 37%, LDL cholesterol was reduced by 29%, and high-density lipoprotein (HDL)–cholesterol levels were increased by 20%. 29 Red yeast rice reduced lipid ratios including LDL-cholesterol levels, total cholesterol/HDL cholesterol, LDL cholesterol/HDL cholesterol, and apolipoprotein B/apolipoprotein A-I in hypercholesterolemic patients. 30 A meta-analysis reviewed the efficacy of 3 red yeast rice preparations ( Cholestin , Xuezhikang , and Zhibituo ) from 93 randomized trials (9,625 patients). When compared with placebo, red yeast rice treatment reduced serum total cholesterol, triglycerides, and LDL-cholesterol levels, and increased HDL-cholesterol levels. The efficacy of the treatment on lipid modification was comparable with that of the prescription drug products pravastatin, simvastatin, lovastatin, atorvastatin, or fluvastatin. When compared with nonstatin drug therapy, red yeast rice was superior to nicotinate and fish oils, but not to fenofibrate and gemfibrozil. No difference was found between Xuezhikang and Zhibituo in lipid profiles. 31 , 32

Other pharmacologic activity
Bone formation

Statins may reduce the risk of bone fractures, as well as increasing bone formation and bone mass. Red yeast rice stimulated bone formation in rats. 33

Hypertension

An aqueous extract of M. purpureus prevented and reversed fructose-induced hypertension in rats and did not affect blood pressure levels in normotensive rats fed a regular diet. The effect is believed to be associated with the GABA contents. 3

Dosage

Red yeast rice is available commercially, primarily in 600 mg capsule form. Most manufacturers suggest a dosage regimen of 2 capsules twice a day by mouth for a total dose of 2,400 mg/day. Commercial OTC products often contain coenzyme Q 10 to supplement the low levels of this enzyme found in patients with statin myopathy. 34 Past clinical trials have used dosages of 2,400 mg/day. 35 , 36

Pregnancy/Lactation

Avoid use during pregnancy and lactation. The major ingredient in red yeast rice is monacolin K, which is also known as mevinolin or lovastatin and has statin-like activity. Statins have been identified as potential teratogens based on theoretical considerations and in small case studies. 37 CNS and limb defects have been reported in newborns exposed to statins in utero. 38

Interactions

Cholesterol-lowering medications

Avoid using red yeast rice with statin medications because of additive effects, which can increase the risk of liver damage and rhabdomyolysis.

Cyclosporine

A case report has been documented with red yeast rice–induced rhabdomyolysis in a stable renal transplant recipient. 39

Grapefruit juice

Grapefruit juice may increase blood levels of the active ingredient in red yeast rice, leading to greater adverse reactions and potential liver damage.

Adverse Reactions

Avoid use if the patient is hypersensitive to any components of red yeast rice. Anaphylactic reactions in certain patient populations have been reported. 40 , 41 Because red yeast rice depletes tissue of coenzyme Q 10 , which may increase the risk of statin-induced myopathy, patients with muscle damage caused by statins should avoid its use. 34 , 42

Meta-analysis of the efficacy of 3 red yeast rice preparations ( Cholestin , Xuezhikang , and Zhibituo ) from 93 randomized trials (9,625 patients) documented no serious adverse reactions. The most common adverse reactions included dizziness, decreased appetite, nausea, stomachache, abdominal distension, and diarrhea. A small number of patients suffered from increased serum BUN and ALT levels. 32

Toxicology

The nephrotoxic mycotoxin citrinin has been isolated from some strains of M. purpureus and M. ruber . 10 , 43

Toxicity studies on Monascus show no toxicity at doses much greater than typical dosing in both long- and short-term studies. In rats fed Monascus 50 times the human dose, results showed no abnormalities in behavior or blood and urine testing. One to two percent of HMG-CoA reductase users in general experience hepatotoxicity and myopathy. 27 Monascus is not recommended for use in patients with liver disease.

Bibliography

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