Red Yeast Rice

Last Updated: September 28 2022

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.

Red Yeast Rice is most often used for

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Skeletal Muscle Interactions


Cholesterol uptake

As cholesterol synthesis is comparatively lower in skeletal muscle relative to other organs,[1] it is thought to be dependent on serum uptake.[2] The fibroblast LDL receptor appears to be half-saturated at subphysiological levels of LDL, around 30 μg/mL[3] and deletion of this receptor doesn't appear to influence intracellular cholesterol significantly.[4][2]

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[5] and the liver's upregulation is known to reduce circulating LDL-C via increased uptake.[6]

Other mechanisms of cholesterol uptake from LDL-C include the lipoprotein lipase (LPL) receptor[7][8] which although is the rate-limiting enzyme for triglyceride uptake into a cell is not the rate-limit for cholesterol uptake;[2] at least with simvastatin, muscle cells can uptake 30% more cholsterol following statin usage (mouse study) without affecting cholesterol concentrations.[2] This study, despite failing to note an increase in cholesterol concentrations alongside the increased uptake, noted that simvastatin increased mitochondrial content of skeletal muscles;[2] although due to decreases in ubiquinone this may be a false positive for mitochondrial function.[9] Increased cholesterol concentration, however, has been noted in human interventions with simvastatin at 80mg[9] and this study noted that other sterols, such as campesterol, also increased.[9]

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)[10] similar to an increase in LPL on cardiomyocytes.[11] Furthermore, competitive athletes who have increased LDL expression[12] seem to be more likely to have complications from statin usage.[13] .

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.



Phenotypically speaking, statin-induced myopathy appears to be a deficiency in the regenerative capacity of microlesions[14][15] which is supported by increased serum creatine kinase (indicative of muscle protein breakdown) up to 48-72 hours after tissue damaging exercise[16][17] and how intense exercise is an independent risk factor for statin induced myopathy.[18]

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).[19] 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[20] 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,[1] myopathy appears to be independent of reduced cholesterol concentrations[19]).

Less GGPP in a cell system is associated with less protein synthesis due to reduced RhoA (a small protein kinase)[21] and may inhibit complex IV of the mitochondria, reducing cellular ATP levels.[22] RhoA is known to be reduced due to less Melavonate availability[23] and lower RhoA concentrations are associated with muscle cell catabolism.[24]

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.[25]



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;[26] this study noted comparable increases with lovastain and pravastatin, both of which outperformed atorvastatin and simvastatin which comparatively outperformed no statin usage.[26] 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[16] or downhill treadmill walking[17] 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[18]).

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[27] due to being selectively taken up by OATP1B1,[28] a transport expressed on hepatocytes almost exclusively;[29] thus limiting the muscle exposure to pravastatin.[30] Although pravastatin would induce the same effects if cultured in vitro,[20] 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.[31]

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.[32]

SEPN1-related myopathies (genetic faults) are phenotypically similar to statin-induced myopathies[33][34] and the reduced amount of selenoprotein N (which is localized in the endoplasmic reticulum of muscle[35] and accumulates in damaged muscle and recruit satellite cells[36]) 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[16][17]) 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[33] and is not present in high levels in adult skeletal muscle without physical injury,[37] 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.[38]

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).


Interactions with Hormones



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.[15][39] 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[40]

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[41] which has been seen in rats (simvastatin)[42] although failed to be replicated with simvastatin.[43]


Peripheral Organ Systems



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).[44] 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",[45][46] 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]


Nutrient-Nutrient Interactions



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.[9]



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.[9] Coingestion of plant sterols (or stanols) with statin usage appears to induce further decreases in serum cholesterol.[49]



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


Safety and Toxicology



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].



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]


Case 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]

2.^Yokoyama M, Seo T, Park T, Yagyu H, Hu Y, Son NH, Augustus AS, Vikramadithyan RK, Ramakrishnan R, Pulawa LK, Eckel RH, Goldberg IJEffects of lipoprotein lipase and statins on cholesterol uptake into heart and skeletal muscleJ Lipid Res.(2007 Mar)
9.^Päivä H, Thelen KM, Van Coster R, Smet J, De Paepe B, Mattila KM, Laakso J, Lehtimäki T, von Bergmann K, Lütjohann D, Laaksonen RHigh-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trialClin Pharmacol Ther.(2005 Jul)
10.^Levak-Frank S, Radner H, Walsh A, Stollberger R, Knipping G, Hoefler G, Sattler W, Weinstock PH, Breslow JL, Zechner RMuscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic miceJ Clin Invest.(1995 Aug)
11.^Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, Seo T, Hu Y, Lutz EP, Merkel M, Bensadoun A, Homma S, Goldberg IJLipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathyJ Clin Invest.(2003 Feb)
12.^Herbert PN, Bernier DN, Cullinane EM, Edelstein L, Kantor MA, Thompson PDHigh-density lipoprotein metabolism in runners and sedentary menJAMA.(1984 Aug 24-31)
14.^Moosmann B, Behl CSelenoprotein synthesis and side-effects of statinsLancet.(2004 Mar 13)
16.^Parker BA, Augeri AL, Capizzi JA, Ballard KD, Troyanos C, Baggish AL, D'Hemecourt PA, Thompson PDEffect of statins on creatine kinase levels before and after a marathon runAm J Cardiol.(2012 Jan 15)
17.^Thompson PD, Zmuda JM, Domalik LJ, Zimet RJ, Staggers J, Guyton JRLovastatin increases exercise-induced skeletal muscle injuryMetabolism.(1997 Oct)
18.^Thompson PD, Clarkson P, Karas RHStatin-associated myopathyJAMA.(2003 Apr 2)
19.^Wagner BK, Gilbert TJ, Hanai J, Imamura S, Bodycombe NE, Bon RS, Waldmann H, Clemons PA, Sukhatme VP, Mootha VKA small-molecule screening strategy to identify suppressors of statin myopathyACS Chem Biol.(2011 Sep 16)
21.^Dvoracek LA, Kreisberg JI, McKinney J, Schmid G, Francis AD, Kacmarik KL, Lee HM, Detrick MS, Primerano DA, Santanam N, Kreisberg RLovastatin 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 pyrophosphateAtherosclerosis.(2010 Jan)
22.^Duncan AJ, Hargreaves IP, Damian MS, Land JM, Heales SJDecreased ubiquinone availability and impaired mitochondrial cytochrome oxidase activity associated with statin treatmentToxicol Mech Methods.(2009 Jan)
23.^Henneman L, Schneiders MS, Turkenburg M, Waterham HRCompromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiencyJ Inherit Metab Dis.(2010 Oct)
24.^McClung JM, Thompson RW, Lowe LL, Carson JARhoA expression during recovery from skeletal muscle disuseJ Appl Physiol.(2004 Apr)
25.^Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, Kishi S, Yamashita M, Phillips PS, Sukhatme VP, Lecker SHThe muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicityJ Clin Invest.(2007 Dec)
26.^Riechman SE, Andrews RD, Maclean DA, Sheather SStatins and dietary and serum cholesterol are associated with increased lean mass following resistance trainingJ Gerontol A Biol Sci Med Sci.(2007 Oct)
28.^Ieiri I, Tsunemitsu S, Maeda K, Ando Y, Izumi N, Kimura M, Yamane N, Okuzono T, Morishita M, Kotani N, Kanda E, Deguchi M, Matsuguma K, Matsuki S, Hirota T, Irie S, Kusuhara H, Sugiyama YMechanisms of Pharmacokinetic Enhancement Between Ritonavir and Saquinavir; Micro/Small Dosing Tests Using Midazolam (CYP3A4), Fexofenadine (p-Glycoprotein), and Pravastatin (OATP1B1) as Probe DrugsJ Clin Pharmacol.(2013 Feb 4:1-16)
29.^Herfindal L, Myhren L, Kleppe R, Krakstad C, Selheim F, Jokela J, Sivonen K, Døskeland SONostocyclopeptide-M1: a potent, nontoxic inhibitor of the hepatocyte drug transporters OATP1B3 and OATP1B1Mol Pharm.(2011 Apr 4)
30.^Pierno S, De Luca A, Tricarico D, Ferrannini E, Conte T, D'Alò G, Camerino DCExperimental evaluation of the effects of pravastatin on electrophysiological parameters of rat skeletal musclePharmacol Toxicol.(1992 Nov)
31.^Medina MW, Theusch E, Naidoo D, Bauzon F, Stevens K, Mangravite LM, Kuang YL, Krauss RMRHOA is a modulator of the cholesterol-lowering effects of statinPLoS Genet.(2012)
33.^Castets P, Lescure A, Guicheney P, Allamand VSelenoprotein N in skeletal muscle: from diseases to functionJ Mol Med (Berl).(2012 Oct)
34.^Moghadaszadeh B, Petit N, Jaillard C, Brockington M, Quijano Roy S, Merlini L, Romero N, Estournet B, Desguerre I, Chaigne D, Muntoni F, Topaloglu H, Guicheney PMutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndromeNat Genet.(2001 Sep)
35.^Lescure A, Gautheret D, Carbon P, Krol ANovel selenoproteins identified in silico and in vivo by using a conserved RNA structural motifJ Biol Chem.(1999 Dec 31)
36.^Castets P, Bertrand AT, Beuvin M, Ferry A, Le Grand F, Castets M, Chazot G, Rederstorff M, Krol A, Lescure A, Romero NB, Guicheney P, Allamand VSatellite cell loss and impaired muscle regeneration in selenoprotein N deficiencyHum Mol Genet.(2011 Feb 15)
38.^Hornberger TA, McLoughlin TJ, Leszczynski JK, Armstrong DD, Jameson RR, Bowen PE, Hwang ES, Hou H, Moustafa ME, Carlson BA, Hatfield DL, Diamond AM, Esser KASelenoprotein-deficient transgenic mice exhibit enhanced exercise-induced muscle growthJ Nutr.(2003 Oct)
39.^Köhrl J, Brigelius-Flohé R, Böck A, Gärtner R, Meyer O, Flohé LSelenium in biology: facts and medical perspectivesBiol Chem.(2000 Sep-Oct)
40.^Miller BT, Ueta CB, Lau V, Jacomino KG, Wasserman LM, Kim BWStatins and downstream inhibitors of the isoprenylation pathway increase type 2 iodothyronine deiodinase activityEndocrinology.(2012 Aug)
41.^Demke DMDrug interaction between thyroxine and lovastatinN Engl J Med.(1989 Nov 9)
42.^Smith PF, Grossman SJ, Gerson RJ, Gordon LR, Deluca JG, Majka JA, Wang RW, Germershausen JI, MacDonald JSStudies on the mechanism of simvastatin-induced thyroid hypertrophy and follicular cell adenoma in the ratToxicol Pathol.(1991)
47.^Gordon RY1, Cooperman T, Obermeyer W, Becker DJMarked variability of monacolin levels in commercial red yeast rice products: buyer bewareArch Intern Med.(2010 Oct 25)
48.^Childress L1, Gay A, Zargar A, Ito MKReview of red yeast rice content and current Food and Drug Administration oversightJ Clin Lipidol.(2013 Mar-Apr)
50.^Holstein SA, Kuder CH, Tong H, Hohl RJPleiotropic effects of a schweinfurthin on isoprenoid homeostasisLipids.(2011 Oct)
51.^Endo A, Kuroda MCitrinin, an inhibitor of cholesterol synthesisJ Antibiot (Tokyo).(1976 Aug)
52.^Dönmez-Altuntas H1, Dumlupinar G, Imamoglu N, Hamurcu Z, Liman BCEffects of the mycotoxin citrinin on micronucleus formation in a cytokinesis-block genotoxicity assay in cultured human lymphocytesJ Appl Toxicol.(2007 Jul-Aug)
53.^Sabater-Vilar M1, Maas RF, Fink-Gremmels JMutagenicity of commercial Monascus fermentation products and the role of citrinin contaminationMutat Res.(1999 Jul 21)
54.^Smith DJ1, Olive KEChinese red rice-induced myopathySouth Med J.(2003 Dec)
55.^Vercelli L, Mongini T, Olivero N, Rodolico C, Musumeci O, Palmucci LChinese red rice depletes muscle coenzyme Q10 and maintains muscle damage after discontinuation of statin treatmentJ Am Geriatr Soc.(2006 Apr)
56.^Mueller PSSymptomatic myopathy due to red yeast riceAnn Intern Med.(2006 Sep 19)
57.^Lapi F, Gallo E, Bernasconi S, Vietri M, Menniti-Ippolito F, Raschetti R, Gori L, Firenzuoli F, Mugelli A, Vannacci AMyopathies associated with red yeast rice and liquorice: spontaneous reports from the Italian Surveillance System of Natural Health ProductsBr J Clin Pharmacol.(2008 Oct)
58.^Prasad GV1, Wong T, Meliton G, Bhaloo SRhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipientTransplantation.(2002 Oct 27)
59.^Roselle H, Ekatan A, Tzeng J, Sapienza M, Kocher JSymptomatic hepatitis associated with the use of herbal red yeast riceAnn Intern Med.(2008 Oct 7)