NMR evaluation of total statin content and HMG-CoA reductase inhibition in red yeast rice (Monascus spp.) food supplements
© Lachenmeier et al; licensee BioMed Central Ltd. 2012
Received: 18 January 2012
Accepted: 22 March 2012
Published: 22 March 2012
Red yeast rice (i.e., rice fermented with Monascus spp.), as a food supplement, is claimed to be blood cholesterol-lowering. The red yeast rice constituent monacolin K, also known as lovastatin, is an inhibitor of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase. This article aims to develop a sensitive nuclear magnetic resonance (NMR) method to determine the total statin content of red yeast rice products.
The total statin content was determined by a 400 MHz 1H NMR spectroscopic method, based on the integration of the multiplet at δ 5.37-5.32 ppm of a hydrogen at the hexahydronaphthalene moiety in comparison to an external calibration with lovastatin. The activity of HMG-CoA reductase was measured by a commercial spectrophotometric assay kit.
The NMR detection limit for total statins was 6 mg/L (equivalent to 0.3 mg/capsule, if two capsules are dissolved in 50 mL ethanol). The relative standard deviations were consistently lower than 11%. The total statin concentrations of five red yeast rice supplements were between 1.5 and 25.2 mg per specified daily dose. A dose-dependent inhibition of the HMG-CoA reductase enzyme activity by the red yeast rice products was demonstrated.
A simple and direct NMR assay was developed to determine the total statin content in red yeast rice. The assay can be applied for the determination of statin content for the regulatory control of red yeast rice products.
The fermentation products of Monascus, have been used as food and traditional Chinese medicine for over 1000 years . The products are called "Hong Qu", "Hon-Chi", "Anka" or "Ang-kak" in China and Taiwan, "Beni Koji" or "red Koji" in Japan. In Europe, the products are called "red yeast rice", "red rice", "red mould rice" or "red Chinese rice". It should be noted that the designation "yeast" is taxonomically not correct . Red yeast rice is used as an additive for the colouring, flavouring and preservation of foods, which may be permitted in some Asian countries but not in Europe. Currently red yeast rice products are predominantly marketed as food supplements, primarily sold through the Internet .
Monacolin compounds are formed by Monascus during the fermentation process. They cause a reversible competitive inhibition of the microsomal hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase; thus, they prevent the reduction of HMG-CoA to mevalonic acid and the formation of cholesterol . The major Monascus metabolite is monacolin K, which is structurally identical to lovastatin, the first statin drug introduced into the market [3, 4]. The red yeast rice products that are currently marketed as food supplements differ from the traditional red yeast rice that is sold in Chinese groceries. The food supplements are manufactured using selected Monascus strains under carefully controlled and fully monitored conditions to increase the monacolin content .
The European Food Safety Authority (EFSA) has recently provided a scientific opinion on the health claims related to monacolin K from red yeast rice . The opinion was based on two double-blind, placebo-controlled human intervention studies, which demonstrated a significant reduction in total cholesterol concentrations in the red yeast rice treatment groups compared to the placebo groups [7, 8]. Besides these clinical trials, other studies also supported the efficacy of red yeast rice [9–11], as reviewed by Liu et al.. A study regarding cholesterol synthesis in human hepatic cells in vitro showed that the inhibition of HMG-CoA reductase was facilitated by red yeast rice preparations, like lovastatin . The monacolin K prepared from red yeast rice was effective for the maintenance of normal blood LDL-cholesterol levels . As the EFSA  has not classified such products as food or medicine, the EFSA's opinion should not be interpreted as an approval of red yeast rice for food or medicinal use.
Red yeast rice is expected to have the adverse effects of its constituent lovastatin, including an increased risk of myopathy [14–18], acute rhabdomyolysis , symptomatic hepatitis  and anaphylactic reactions . Drug interactions may influence liver enzyme expression leading to a lower clearance and elevated plasma concentration of lovastatin (e.g., by inhibition of cytochrome P450 enzyme CYP3A4) [19, 22]. When lovastatin is administered with food, the intestinal absorption may be increased by about 50%, while pectin and oat bran may decrease its absorption [22–24]. The excessive use of grapefruit juice may inhibit CYP3A4 and lead to higher plasma concentrations of lovastatin [25, 26].
Accurate determination of the statin content in red yeast rice products would be necessary for the regulatory control. Previous analytical approaches mainly used high-performance liquid chromatography (HPLC) with diode array or mass spectrometric detectors [27–33]. Song et al. suggested a flow injection tandem mass spectrometry for screening analysis. Chromatographic and mass spectrometric methods have some problems in separating over 14 monacolins and avoiding co-eluting interferences that could cause overestimation of the quantities of the analytes . Furthermore, an equilibrium exists between monacolin K and its lactone ring opened hydroxy acid form (ratio between 2:1 and 3:2), which can be chromatographically separated . For this reason, the total monacolin content should be determined for the evaluation of such products [28, 32, 35]. The exclusive determination of the lactone form of monacolin K could underestimate the pharmacological activity. Accurate quantification for the hydroxy acid and other monacolin isomers was difficult because of the lack of commercial reference standards .
In this study, we overcome these problems by nuclear magnetic resonance (NMR) spectroscopy, which is advantageous for quantitative pharmaceutical analysis due to its high selectivity . Dependent on the selected chemical shifts for quantification, such as protons at the hexahydronaphthalene moiety common to all first generation statins , the determination of total statins appears to be feasible with NMR without reference standards for each specific compound. A commercial HMG-CoA reductase assay kit was used to confirm the effects of the red yeast rice. The samples purchased over the Internet were evaluated by these methods.
Materials and methods
Samples and sample preparation
An internet search was conducted in November 2011 to identify the red yeast rice products that were offered at German speaking websites to German speaking consumers (for exact methodology, see Löbell-Behrends et al.[38, 39]). None of the identified products was available in conventional retail stores. We purchased five different products, all were marketed to German consumers as food supplements in capsule form (i.e., the red yeast rice is provided in powder form inside a capsule).
For sample preparation, the content of two capsules (about 0.9 g) was dissolved in 50 mL of absolute ethanol (Merck, Darmstadt, Germany). An aliquot of 170 μL of this solution was mixed with 370 μL of distilled water and 60 μL of pH 7.4 NMR buffer (1.5 M KH2PO4 in D2O, 0.1% 3-(trimethylsilyl)-propionate acid-d4 (TSP), 3 mM NaN3). The mixture was poured into an NMR tube and directly measured. A lovastatin (Teva, Debrecen, Hungary) stock solution (500 mg/L) was prepared in absolute ethanol. For calibration, standards were prepared by diluting the lovastatin stock solution with ethanol (40% vol).
All 1H NMR measurements were performed using a Bruker Avance 400 Ultrashield spectrometer (Bruker BioSpin, Rheinstetten, Germany) equipped with a 5-mm SEI probe with Z-gradient coils and an Automatic Sample Changer B-ACS 120 (Bruker BioSpin, Rheinstetten, Germany). All spectra were acquired at 300.0 K.
The NMR method was modified from our previous work for testing other products . Two successive 1H NMR experiments were used for the measurement of each sample. First, the standard Bruker BioSpin water pre-saturation pulse program ZGPR was used to suppress only the signal of OH-protons. The relaxation delay (RD), and acquisition time (AQ) were set to 4 s and 3.99 s, respectively, resulting in a total recycle time of 7.99 s. After application of four dummy scans (DS), eight free induction decays (FIDs) (number of scans, NS = 8) were collected into a time domain (TD) of 65536 (65 k) complex data points using a 20.5187 ppm spectral width and a receiver gain of 1. The FIDs were multiplied with an exponential function corresponding to a line broadening of 1 Hz prior to Fourier transformation. Second, 8-fold suppression of water and ethanol was performed with the frequencies identified in the first experiment (Bruker sequence NOESYGPPS1D). The settings for the parameters RD, P(90°), AQ, and TD were kept similar to the ones from the first experiment, DS = 4 and NS = 32 were used and the mixing time (tm) was set to 10 ms.
The data were acquired automatically under the control of ICON-NMR (Bruker BioSpin, Rheinstetten, Germany), requiring about 12 min per sample. All NMR spectra were phased, baseline-corrected and integrated using Topspin 3.1 (Bruker BioSpin, Rheinstetten, Germany). For quantification, linear calibration curves were constructed from the lovastatin standards by integrating the multiplet at δ 5.37-5.32 ppm against TSP as an intensity reference. All measurements were done in five replicates including sample preparation. For 1H NMR spectral prediction, the software ChemBioDraw 12.0 (CambridgeSoft, Cambridge, UK) was used. The spectral prediction was performed according to Schaller et al..
Validation of NMR method
For method validation, standard solutions and authentic red yeast rice samples were analyzed several times on one day (intraday, n = 5) and over five consecutive days (interday, n = 10). The linearity of the calibration curves was evaluated in the range covering the concentrations found in the investigated products. The recovery rate was ascertained by adding lovastatin standard solution at two different concentrations to a real sample. The limits of detection (LOD) and quantification (LOQ) were calculated from the residual standard deviation of the regression line .
HMG-CoA reductase assay
The HMG-CoA reductase (HMGR) assay kit #CS1090 from Sigma-Aldrich (Saint Louis, MO, USA) was used. The procedure was modified from Perchellet et al., and according to the manufacturer's instructions, with the exception of an additional dilution 1:3 in assay buffer to facilitate the use of standard 1 cm cuvettes (i.e., 3 mL final volume instead of 1 mL volume). The inhibitor solution (pravastatin) provided with the kit was used as positive control.
The red yeast rice sample solutions prepared for NMR analysis were used for the assay in appropriate dilution. Spectrophotometric measurements were performed on a Perkin Elmer Lambda 20 dual beam spectrometer (Perkin Elmer, Rodgau, Germany) at 37°C. The spectrometer was operated with the Perkin Elmer UV WinLab software (version 2.85.04) in time drive mode. The absorbance at 340 nm was monitored at a time interval of 1.00 s for a total time of 15 min. The slit width was 1.00 nm and the response time 0.1 s.
All data were evaluated using Origin V.7.5 (OriginLab, Northampton, USA). Data are presented as means and standard deviations among replicates. Linear regression analysis was used to compare NMR responses and concentrations. P < 0.05 was considered statistically significant.
Results and discussion
NMR quantification results
Results of method validation for monacolin K (lovastatin) using 1H NMR
Investigated linear working range
5 - 100 mg/L
Limit of detectiona
6 mg/L (0.33 mg/capsulec)
Limit of quantitationa
13 mg/L (0.72 mg/capsulec)
104% (at 50 mg/L)
113% (at 20 mg/L)
Results of the quantitative 1H NMR determination of total statins in red yeast rice products
Total statins (NMR)
Labelling of monacolin K
(mg/daily dose) b
Red rice, food supplement, 330 mg capsules (in German)
1.5 ± 0.1
1.5 - 4.5
Red yeast rice, food supplement, 600 mg capsules (in English)
USA with UK labelling
3.3 ± 0.4
Red yeast rice, herbal supplement, 330 mg capsules (in English)
5.3 ± 0.6
Red yeast rice, dietary supplement, 600 mg capsules (in English)
6.3 ± 0.2
12.6 - 25.2
Red yeast rice, food supplement, 600 mg capsules (in French)
8.0 ± 0.6
16.0 - 24.0
HMG-CoA reductase inhibition
A simple and direct NMR assay was developed to determine the total statin content in red yeast rice. The assay can be applied for the determination of statin content for the regulatory control of red yeast rice products.
The authors warmly thank Hannelore Heger for excellent technical assistance. The study was funded by a grant from the Ministry of Rural Affairs and Consumer Protection of the German federal state of Baden-Württemberg (Stuttgart, Germany). The funder played no role in study design, collection, data analysis and interpretation, report writing and decision to submit the paper for publication. This paper does not necessarily represent the views of the Ministry of Rural Affairs and Consumer Protection.
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