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Red Yeast Rice

Red Yeast Rice (RYR) is a rice product fermented by bacteria that contains the drug lovastatin, and is currently the most effective naturally occurring statin. It is able, like most statins, to reduce circulating cholesterol levels.

Our evidence-based analysis on red yeast rice features 59 unique references to scientific papers.

Kamal Patel
Research analysis led by Kamal Patel.
All content reviewed by the Examine.com Team. Published: Nov 16, 2014
Last Updated:

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Things To Know & Note

Primary Function:

Also Known As

RYR

Do Not Confuse With

Lovastatin (active ingredient), Monascus purpureus (mold used in processing)

Caution Notice

Examine.com Medical Disclaimer

  • It appears that the FDA (American) has banned sales of any RYR product with 'non-negligible' levels of Monacolin K/Lovastatin[1] due to the position of Lovastatin as a pharmaceutical drug;[2] this significantly reduces the supposed benefits associated with red yeast extract

Scientific Research on Red Yeast Rice

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1Skeletal Muscle Interactions

1.1Cholesterol uptake

As cholesterol synthesis is comparatively lower in skeletal muscle relative to other organs,[3] it is thought to be dependent on serum uptake.[4] The fibroblast LDL receptor appears to be half-saturated at subphysiological levels of LDL, around 30 μg/mL[5] and deletion of this receptor doesn't appear to influence intracellular cholesterol significantly.[6][4]

Inhibition of HMG-CoA (statin usage) is able to induce SREBP2 in adipose and liver cells to increase cholesterol uptake via increasing the expression of the LDL receptor[7] and the liver's upregulation is known to reduce circulating LDL-C via increased uptake.[8]

Other mechanisms of cholesterol uptake from LDL-C include the lipoprotein lipase (LPL) receptor[9][10] which although is the rate-limiting enzyme for triglyceride uptake into a cell is not the rate-limit for cholesterol uptake;[4] at least with simvastatin, muscle cells can uptake 30% more cholsterol following statin usage (mouse study) without affecting cholesterol concentrations.[4] This study, despite failing to note an increase in cholesterol concentrations alongside the increased uptake, noted that simvastatin increased mitochondrial content of skeletal muscles;[4] although due to decreases in ubiquinone this may be a false positive for mitochondrial function.[11] Increased cholesterol concentration, however, has been noted in human interventions with simvastatin at 80mg[11] and this study noted that other sterols, such as campesterol, also increased.[11]

It should be noted that gross overexpression of LPL in skeletal muscle may cause a myopathy, though to be related to increased fatty acid influx (as LPL mediates fatty acids and cholesterol)[12] similar to an increase in LPL on cardiomyocytes.[13] Furthermore, competitive athletes who have increased LDL expression[14] seem to be more likely to have complications from statin usage.[15]

Cholesterol uptake into skeletal muscle cells (myocytes) appears to be mediated by both LPL and the LDL receptor, with statin usage increasing the activity of the LDL receptor

1.2Myopathy

Phenotypically speaking, statin-induced myopathy appears to be a deficiency in the regenerative capacity of microlesions[16][17] which is supported by increased serum creatine kinase (indicative of muscle protein breakdown) up to 48-72 hours after tissue damaging exercise[18][19] and how intense exercise is an independent risk factor for statin induced myopathy.[20]

Lovastatin is an HMG-CoA reductase inhibitor, preventing the conversion of HMG-CoA into Melavonate (rate limiting substrate in cholesterol synthesis); the Mevalonate pathway proceed unilaterally until it reaches the substrate Farsenyl Pyrophosphate (FPP) where it can then branch off into several alternate pathways. Although inhibition of HMG-CoA reduces all of these pathways, restoring cholesterol synthesis after this locus point by introducing squalene or cholesterol itself does not attenuate myopathy (using ATP reductions as a surrogate marker) while this myopathy appears to be dependent on reduced Geranylgeranyl Pyrophosphate (GGPP).[21] GGPP is thought to be a main target molecule for statin-related myopathy as it is already expressed to a lower degree in skeletal muscle[22] which may explain the relative sensitivity for complications in skeletal muscle relative to other organs (although cholesterol synthesis is inherently lowest in heart and skeletal muscle tissue,[3] myopathy appears to be independent of reduced cholesterol concentrations[21]).

Less GGPP in a cell system is associated with less protein synthesis due to reduced RhoA (a small protein kinase)[23] and may inhibit complex IV of the mitochondria, reducing cellular ATP levels.[24] RhoA is known to be reduced due to less Melavonate availability[25] and lower RhoA concentrations are associated with muscle cell catabolism.[26]

Myopathy from lovastatin appears to be associated with reducing GGPP (a consequence of inhibiting HMG-CoA, the target enzyme of statins) and independent of the reduction in cholesterol per se

Lovastatin is also known to induce atrogin-1, a protein that mediates protein catabolism and this induction of atrogin-1 is ablated by excessive incubation of PGC-1a.[27]

1.3Hypertrophy

One study (otherwise healthy men aged 60-69) that noted that cholesterol was linearly associated with more lean mass gain in older individuals on a standardized diet and given resistance training noted that usage of lovastatin (in the recommended range) was associated with more muscle building than persons not using statins;[28] this study noted comparable increases with lovastain and pravastatin, both of which outperformed atorvastatin and simvastatin which comparatively outperformed no statin usage.[28] The authors hypothesized this was a recompensatory effect from the known ability of statin drugs to augment exercise-induced muscle injury as assessed by marathons[18] or downhill treadmill walking[19] and when measured 48-72 hours after (intense exercise is also an independent risk factor for myopathy from statins, suggestive of augmenting muscle damage or attenuating the rate of repair[20]).

One study suggests that chronic usage of statin drugs and pairing statins with exercise can increase lean mass accrual from exercise, apparently synergistic with dietary and serum cholesterol. Although statins during exercise are not well studied, they appear to reduce the rate of muscle regeneration

The connection between GGPP and RhoA is unlikely to explain the observed reactions as there are differences between lovastatin and pravastatin, as the latter is known to not be taken up into myocytes to a large degree[29] due to being selectively taken up by OATP1B1,[30] a transport expressed on hepatocytes almost exclusively;[31] thus limiting the muscle exposure to pravastatin.[32] Although pravastatin would induce the same effects if cultured in vitro,[22] it does not appear to reach skeletal muscle well after ingestion.

The only possible link here is that cholesterol ester and free cholesterol influx into a cell (thought to be anabolic to skeletal muscle) is inversely dependent on RhoA, being increased with lower RhoA concentrations.[33]

Reductions of GGPP and, subsequently, RhoA are a possible explanation for the observed hypertrophic response to statins but cannot explain the difference between pravastatin and lovastatin; these reductions are also inherently catabolic

Another possible explanation is using Selenoproteins (proteins made with selenium as a component) and particularly Selenoprotein N, encoded by the SEPN1 gene; due to HMG-CoA inhibition, there is less isopentenylpyrophosphate (IPP) availability (in the cholesterol biosynthetic chain after mevalonate) and IPP appears to be critical for a selenocysteine transfer RNA to make selenoproteins.[34]

SEPN1-related myopathies (genetic faults) are phenotypically similar to statin-induced myopathies[35][36] and the reduced amount of selenoprotein N (which is localized in the endoplasmic reticulum of muscle[37] and accumulates in damaged muscle and recruit satellite cells[38]) correlates well with the phenotype observed in statin-induced and SEPN1 related myopathy as the observed reduced rate of tissue regeneration (evidence by lovastatin increasing serum creatine kinase 48-72 hours after exericse, but not immediately after[18][19]) is more indicative of reduced repair rates than of inducing damage.

Furthermore, although ablation of SEPN1 and reduced selenoprotein N is not adverse to muscle growth per se[35] and is not present in high levels in adult skeletal muscle without physical injury,[39] introduction of a mutant selenocysteine tRNA to reduce selenoprotein amounts, in rats, is associated with a 50% increase in muscle protein synthesis that is mTOR and exercise dependent.[40]

Selenoprotein deficiency appears to be somewhat related to both myopathy as well as enhanced exercise-induced hypertrophy, and statins may reduce cellular selenoprotein concentrations. This seems to correlate better with the observed effects of statins on muscle protein synthesis, but assumes that a hormetic response occurs (this hypothesized hormetic response that ultimately builds muscle is not known yet)

2Interactions with Hormones

2.1Thyroid

Thyroid deiodinases are selenoproteins, which appears to generally be reduced following statin induced inhibition of HMG-CoA by limiting the amount of IPP available for selenocysteine tRNA.[17][41] Despite this, it has been noted that lovastatin and IPP inhibitors increase the activity of type 2 iodothyronine selenodeiodinase (D2) in brown adipose tissue of mice and in vitro[42]

In hypothyroid patients, there appears to be some case studies noting a decrease in T4 and increase in TSH in response to lovastatin paired with thyroxine[43] which has been seen in rats (simvastatin)[44] although failed to be replicated with simvastatin.[45]

3Peripheral Organ Systems

3.1Liver

Red yeast rice which contains monacolin (especially monacolin K) lowers cholesterol levels by reducing cholesterol synthesis by the liver through inhibiting the rate-limiting step catalyzed by the enzyme 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA).[46] However, since monacolin K is identical to the pharmaceutical known as lovastatin, the FDA has banned sales of red yeast rice which contain non-negligible quantities of monacolin K since it is a "non-approved drug",[2][1] thus red yeast rice as currently marketed in the US may not have these effects on the liver's cholesterol production. However, a study done after the FDA ban found that many red yeast rice products still contain monacolin K at levels which widely vary,[47] and a Freedom of Information Act request to investigate FDA oversite of monacolin K levels has revealed that FDA enforcement of monacolin K levels is lacking.[48]

4Nutrient-Nutrient Interactions

4.1CoQ10

Ubiquinone concentrations in skeletal muscle are known to be reduced with statin usage such as simvastatin (80mg for 8 weeks resulting in a 33.6% reduction) paired with less repiratory chain activity.[11]

4.2Sterols

One study using high dose (80mg) simvastatin and measuring sterol concentrations in muscle cells noted that, despite an increase in cholsterol, dietary campesterol (naturally occurring and common sterol) increased; suggesting statin-induced sterol uptake is general rather than specific to cholesterol.[11] Coingestion of plant sterols (or stanols) with statin usage appears to induce further decreases in serum cholesterol.[49]

4.3Schweinfurthins

Schweinfurthins appear to be synergistic with lovastatin in reducing levels of GGPP in medium.[50]

5Safety and Toxicology

5.1General

Citrinin is a mycotoxin that has been found to be present in some red yeast rice products[47] and has been shown to be nephrotoxic in animals with a median LD50 of 35mg/kg[51].

5.2Genotoxicity

Citrinin, a mycotoxin found in red yeast rice, has been shown to be genotoxic to human lymphocyes at high concentrations (above 60μM) in vitro[52] and mutagenic at concentrations above 0.2μg/g in a Salmonella-hepatocyte assay.[53]

5.3Case Studies

There have been several reports of side effects traditionally associated with statin therapy seen with red yeast rice, such as myopathies[54][55][56][57] (including rhabdomyolysis[58]) and hepatitis.[59]

References

  1. ^ a b FDA Warns Consumers to Avoid Red Yeast Rice Products Promoted on Internet as Treatments for High Cholesterol Products found to contain unauthorized drug.
  2. ^ a b Correspondence.
  3. ^ a b Spady DK, Dietschy JM. Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. J Lipid Res. (1983)
  4. ^ a b c d e Yokoyama M, et al. Effects of lipoprotein lipase and statins on cholesterol uptake into heart and skeletal muscle. J Lipid Res. (2007)
  5. ^ Brown MS, Goldstein JL. Regulation of the activity of the low density lipoprotein receptor in human fibroblasts. Cell. (1975)
  6. ^ Osono Y, et al. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse. J Clin Invest. (1995)
  7. ^ Horton JD, et al. Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2. J Clin Invest. (1998)
  8. ^ Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.
  9. ^ Seo T, et al. Lipoprotein lipase-mediated selective uptake from low density lipoprotein requires cell surface proteoglycans and is independent of scavenger receptor class B type 1. J Biol Chem. (2000)
  10. ^ Merkel M, et al. Inactive lipoprotein lipase (LPL) alone increases selective cholesterol ester uptake in vivo, whereas in the presence of active LPL it also increases triglyceride hydrolysis and whole particle lipoprotein uptake. J Biol Chem. (2002)
  11. ^ a b c d e Päivä H, et al. High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther. (2005)
  12. ^ Levak-Frank S, et al. Muscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic mice. J Clin Invest. (1995)
  13. ^ Yagyu H, et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest. (2003)
  14. ^ Herbert PN, et al. High-density lipoprotein metabolism in runners and sedentary men. JAMA. (1984)
  15. ^ Sinzinger H, O'Grady J. Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. Br J Clin Pharmacol. (2004)
  16. ^ Moosmann B, Behl C. Selenoprotein synthesis and side-effects of statins. Lancet. (2004)
  17. ^ a b Moosmann B, Behl C. Selenoproteins, cholesterol-lowering drugs, and the consequences: revisiting of the mevalonate pathway. Trends Cardiovasc Med. (2004)
  18. ^ a b c Parker BA, et al. Effect of statins on creatine kinase levels before and after a marathon run. Am J Cardiol. (2012)
  19. ^ a b c Thompson PD, et al. Lovastatin increases exercise-induced skeletal muscle injury. Metabolism. (1997)
  20. ^ a b Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. (2003)
  21. ^ a b Wagner BK, et al. A small-molecule screening strategy to identify suppressors of statin myopathy. ACS Chem Biol. (2011)
  22. ^ a b Flint OP, et al. HMG CoA reductase inhibitor-induced myotoxicity: pravastatin and lovastatin inhibit the geranylgeranylation of low-molecular-weight proteins in neonatal rat muscle cell culture. Toxicol Appl Pharmacol. (1997)
  23. ^ Dvoracek LA, et al. Lovastatin inhibits oxidized L-A-phosphatidylcholine B-arachidonoyl-gamma-palmitoyl (ox-PAPC)-stimulated interleukin-8 mRNA and protein synthesis in human aortic endothelial cells by depleting stores of geranylgeranyl pyrophosphate. Atherosclerosis. (2010)
  24. ^ Duncan AJ, et al. Decreased ubiquinone availability and impaired mitochondrial cytochrome oxidase activity associated with statin treatment. Toxicol Mech Methods. (2009)
  25. ^ Henneman L, et al. Compromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency. J Inherit Metab Dis. (2010)
  26. ^ McClung JM, et al. RhoA expression during recovery from skeletal muscle disuse. J Appl Physiol. (2004)
  27. ^ Hanai J, et al. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J Clin Invest. (2007)
  28. ^ a b Riechman SE, et al. Statins and dietary and serum cholesterol are associated with increased lean mass following resistance training. J Gerontol A Biol Sci Med Sci. (2007)
  29. ^ Masters BA, et al. In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes. Toxicol Appl Pharmacol. (1995)
  30. ^ Ieiri I, et al. Mechanisms of Pharmacokinetic Enhancement Between Ritonavir and Saquinavir; Micro/Small Dosing Tests Using Midazolam (CYP3A4), Fexofenadine (p-Glycoprotein), and Pravastatin (OATP1B1) as Probe Drugs. J Clin Pharmacol. (2013)
  31. ^ Herfindal L, et al. Nostocyclopeptide-M1: a potent, nontoxic inhibitor of the hepatocyte drug transporters OATP1B3 and OATP1B1. Mol Pharm. (2011)
  32. ^ Pierno S, et al. Experimental evaluation of the effects of pravastatin on electrophysiological parameters of rat skeletal muscle. Pharmacol Toxicol. (1992)
  33. ^ Medina MW, et al. RHOA is a modulator of the cholesterol-lowering effects of statin. PLoS Genet. (2012)
  34. ^ Baker SK. Molecular clues into the pathogenesis of statin-mediated muscle toxicity. Muscle Nerve. (2005)
  35. ^ a b Castets P, et al. Selenoprotein N in skeletal muscle: from diseases to function. J Mol Med (Berl). (2012)
  36. ^ Moghadaszadeh B, et al. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet. (2001)
  37. ^ Lescure A, et al. Novel selenoproteins identified in silico and in vivo by using a conserved RNA structural motif. J Biol Chem. (1999)
  38. ^ Castets P, et al. Satellite cell loss and impaired muscle regeneration in selenoprotein N deficiency. Hum Mol Genet. (2011)
  39. ^ Selenoprotein N: an endoplasmic reticulum glycoprotein with an early developmental expression pattern.
  40. ^ Hornberger TA, et al. Selenoprotein-deficient transgenic mice exhibit enhanced exercise-induced muscle growth. J Nutr. (2003)
  41. ^ Köhrl J, et al. Selenium in biology: facts and medical perspectives. Biol Chem. (2000)
  42. ^ Miller BT, et al. Statins and downstream inhibitors of the isoprenylation pathway increase type 2 iodothyronine deiodinase activity. Endocrinology. (2012)
  43. ^ Demke DM. Drug interaction between thyroxine and lovastatin. N Engl J Med. (1989)
  44. ^ Smith PF, et al. Studies on the mechanism of simvastatin-induced thyroid hypertrophy and follicular cell adenoma in the rat. Toxicol Pathol. (1991)
  45. ^ Abbasinazari M, Nakhjavani M, Gogani S. The effects of simvastatin on the serum concentrations of thyroid stimulating hormone and free thyroxine in hypothyroid patients treated with levothyroxine. Iran J Med Sci. (2011)
  46. ^ Klimek M1, Wang S, Ogunkanmi A. Safety and efficacy of red yeast rice (Monascus purpureus) as an alternative therapy for hyperlipidemia. P T. (2009)
  47. ^ a b Gordon RY1, et al. Marked variability of monacolin levels in commercial red yeast rice products: buyer beware. Arch Intern Med. (2010)
  48. ^ Childress L1, et al. Review of red yeast rice content and current Food and Drug Administration oversight. J Clin Lipidol. (2013)
  49. ^ de Jong A, et al. Effects of long-term plant sterol or stanol ester consumption on lipid and lipoprotein metabolism in subjects on statin treatment. Br J Nutr. (2008)
  50. ^ Holstein SA, et al. Pleiotropic effects of a schweinfurthin on isoprenoid homeostasis. Lipids. (2011)
  51. ^ Endo A, Kuroda M. Citrinin, an inhibitor of cholesterol synthesis. J Antibiot (Tokyo). (1976)
  52. ^ Dönmez-Altuntas H1, et al. Effects of the mycotoxin citrinin on micronucleus formation in a cytokinesis-block genotoxicity assay in cultured human lymphocytes. J Appl Toxicol. (2007)
  53. ^ Sabater-Vilar M1, Maas RF, Fink-Gremmels J. Mutagenicity of commercial Monascus fermentation products and the role of citrinin contamination. Mutat Res. (1999)
  54. ^ Smith DJ1, Olive KE. Chinese red rice-induced myopathy. South Med J. (2003)
  55. ^ Vercelli L, et al. Chinese red rice depletes muscle coenzyme Q10 and maintains muscle damage after discontinuation of statin treatment. J Am Geriatr Soc. (2006)
  56. ^ Mueller PS. Symptomatic myopathy due to red yeast rice. Ann Intern Med. (2006)
  57. ^ Lapi F, et al. Myopathies associated with red yeast rice and liquorice: spontaneous reports from the Italian Surveillance System of Natural Health Products. Br J Clin Pharmacol. (2008)
  58. ^ Prasad GV1, et al. Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient. Transplantation. (2002)
  59. ^ Roselle H, et al. Symptomatic hepatitis associated with the use of herbal red yeast rice. Ann Intern Med. (2008)

This page is regularly updated, to include the most recently available clinical trial evidence.

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This page features 59 references. All factual claims are followed by specifically-applicable references. Click here to see the full set of references for this page.

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