Flavonoid-statin interactions causing myopathy and the possible significance of OATP transport, CYP450 metabolism and mevalonate synthesis.

3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are a primary treatment for hyperlipidemic cardiovascular diseases which are a leading global cause of death. Statin therapy is life saving and discontinuation due to adverse events such as myotoxicity may lead to unfavourable outcomes. There is no known mechanism for statin-induced myotoxicity although it is theorized that it is due to inhibition of downstream products of the HMG-CoA pathway. It is known that drug-drug interactions with conventional medicines exacerbate the risk of statin-induced myotoxicity, though little attention has been paid to herb-drug interactions with complementary medicines. Flavonoids are a class of phytochemicals which can be purchased as high dose supplements. There is evidence that flavonoids can raise statin plasma levels, increasing the risk of statin-induced myopathy. This could be due to pharmacokinetic interactions involving hepatic cytochrome 450 (CYP450) metabolism and organic anion transporter (OATP) absorption. There is also the potential for flavonoids to directly and indirectly inhibit HMG-CoA reductase which could contraindicate statin-therapy. This review aims to discuss what is currently known about the potential for high dose flavonoids to interact with the hepatic CYP450 metabolism, OATP uptake of statins or their ability to interact with HMG-CoA reductase. Flavonoids of particular interest will be covered and the difficulties of examining herbal products will be discussed throughout.

Medicinal plants and bioactive natural compounds as inhibitors of HMG-CoA reductase: A literature review.

Cardiovascular diseases (CVDs) are one of the most important causes for mortality worldwide. Elevated levels of total cholesterol, and particularly LDL-cholesterol (LDL-C) are the main risk factor for acute myocardial infarction (AMI) and ischemic heart disease. The risk of CVDs could be reduced by decreasing the elevated cholesterol levels. ß-hydroxy ß-methylglutaryl-CoA reductase (HMGCoAR) is the primary and rate-limiting enzyme in the cholesterol biosynthesis pathway. Recently, the crucial role of nutraceuticals in maintaining normal physiological function was established. Nutraceuticals play an important role in preventing several non-communicable diseases such as obesity, CVDs, cancer, diabetes, and reducing hyperlipidemia. Although the effect of nutraceuticals and herbal medicine on CVDs and dyslipidemia was previously investigated thoroughly, the effect of these natural products on HMGCoAR as one of the important enzymes involved in CVDs etiopathogenesis has not yet been investigated. Therefore, the major aim of this paper was to review the effects of nutraceuticals and medicinal plants on HMGCoAR. Results indicate that different types of natural foods, isolated nutrients, herbal products, and dietary supplements as nutraceuticals decrease the expression and activity of HMGCoAR. This review shows that medicinal plants and nutraceuticals could be used to decrease HMGCoAR activity as accessible and convenient and economical natural compounds to prevent dyslipidemia and CVDs.

Anti-HMGCR myopathy presenting with acute systolic heart failure.

Necrotising autoimmune myopathy (NAM) is an immune-mediated myopathy that may be associated with statin use, malignancy or an autoimmune connective tissue disease, but it can also be idiopathic. Anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) myopathy is an extremely rare side effect of statin use, occurring in approximately 2-3 out of every 100 000 patients who use statins. Patients typically present with subacute proximal muscle weakness and creatine kinase levels >10 times the upper limit of normal. The diagnosis is suggested by muscle biopsy showing necrotic fibres with minimal inflammation along with positive anti-HMGCR antibodies. Treatment nearly always requires multiple immunosuppressive agents, the earlier use of which is associated with improved outcomes. Reports of statin-induced NAM leading to heart failure are limited. We present the case of a 69-year-old woman with statin-induced NAM who presented with acute systolic heart failure. Early initiation of high-dose corticosteroids and IVIG resulted in significant improvement in her symptoms.

Antioxidative and Inhibitory Effects of the Fruiting Body of Black Lingzhi Mushroom, Amauroderma rugosum (Agaricomycetes), on LDL Oxidation and HMG-CoA Reductase Activity.

Amauroderma rugosum fruiting bodies possess excellent cardiovascular benefits, including antioxidative, antihyperlipidemic, antihypertensive, antiinflammatory, anti-platelet aggregation, and antithrombotic effects. In this article, we describe our investigations of the in vitro antioxidant activity and in vitro antiatherosclerotic potential through inhibitory effects on low-density lipoprotein (LDL), LDL peroxidation, and 3-hydroxy3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalytic activity using various fruiting body extracts partitioned with an organic solvent. Among 5 extracts/fractions tested, the semipolar ethyl acetate (EA) fraction demonstrated good antioxidant capacity based on total phenolic content, 2,2-diphenyl-1-picrylhydrazyl free radical scavenging, ferrous ion-chelating ability, cupric ion-reducing antioxidant capacity, and lipid peroxidation assays. The EA fraction also showed the strongest inhibitory effect on Cu2+-induced LDL oxidation via thiobarbituric acid reactive substances formation and HMG-CoA reductase activity. Chemical analysis conjointly identified 10 phenolic compounds (4 benzoic acid derivatives, 3 flavonoids, 1 cinnamic acid, 1 hexahydroxydiphenic acid dilactone, and 1 xanthone derivative), some of which play pivotal roles in arresting the physiopathogenesis of atherosclerosis, thereby attenuating the risk of cardiovascular events occurring.

Possible inhibition of hydroxy methyl glutaryl CoA reductase activity by nicotinic acid and ergosterol: as targeting for hypocholesterolemic action.

OBJECTIVE: Coronary artery diseases including atherosclerosis is considered as commonest problem worldwide. Ergosterols are the main components of vegetable oils and nuts. The objective of this study was to evaluate the potential hypoplipidemic and hypocholesterolemic effects of ergosterol in combination with niacin in rats fed high fat diet (HFD). METHODS: Eighty male albino rats were included in this study divided into two main groups: Group I: Normal rats fed standard diet treated with either niacin (8.5 mg /kg b.w) or ergosterol (100 mg/Kg b.w) or both. Group II; rats fed HFD treated with either niacin (8.5 mg /kg b.w) or ergosterol (100 mg/Kg b.w) or both The feeding and treatment lasted for 8 weeks. RESULTS: A significant elevation in the levels of total cholesterol, triacylglycerol, VLDL-c, LDL-c and atherogenic factor (p<0.001) in rats fed on HFD compared with normal control while HDL-c was significantly reduced in HFD rats compared with control group. Supplementation of diet with niacin or ergosterol or combined exerts improvement in the studied parameters by lowering triacylglycerol, total cholesterol, LDL-c and atherogenic factor and elevate HDL-c near to the value of control. Niacin combined with ergosterol were effective in the reduction of hydroxy methyl glutaryl-CoA reducatase (HMGCoA) compared with control (p<0.001). The combined effect was more potent than individual alone. CONCLUSION: Utilization of niacin and ergosterol may prevent the hypercholesterolemia and incidence of coronary heart diseases. These functional foods act as nutriceutical as dyslipidemics.

Lanostane Triterpenes from the Tibetan Medicinal Mushroom Ganoderma leucocontextum and Their Inhibitory Effects on HMG-CoA Reductase and α-Glucosidase.

Sixteen new lanostane triterpenes, ganoleucoins A-P (1-16), together with 10 known tripterpenes (17-26), were isolated from the cultivated fruiting bodies of Ganoderma leucocontextum, a new member of the Ganoderma lucidum complex. The structures of the new compounds were elucidated by extensive spectroscopic analysis and chemical transformation. The inhibitory effects of 1-26 on HMG-CoA reductase and α-glucosidase were tested in vitro. Compounds 1, 3, 6, 10-14, 17, 18, 23, 25, and 26 showed much stronger inhibitory activity against HMG-CoA reductase than the positive control atorvastatin. Compounds 13, 14, and 16 presented potent inhibitory activity against α-glucosidase from yeast with IC50 values of 13.6, 2.5, and 5.9 µM, respectively. In addition, the cytotoxicity of 1-26 was evaluated against the K562 and PC-3 cell lines by the MTT assay. Compounds 1, 2, 6, 7, 10, 12, 16, 18, and 25 exhibited cytotoxicity against K562 cells with IC50 values in the range 10-20 µM. Paclitaxel was used as the positive control with an IC50 value of 0.9 µM. This is the first report of secondary metabolites from this medicinal mushroom.

Coenzyme Q10 and statin-related myopathy.

Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is involved in the production of mevalonic acid in the cholesterol biosynthesis pathway. This pathway also results in the production of other bioactive molecules including coenzyme Q10 (also known as ubiquinone or ubidecarenone). Coenzyme Q10 is a naturally-occurring coenzyme with antioxidant effects that is involved in electron transport in mitochondria and is thought to play a role in energy transfer in skeletal muscle. Muscle-related problems are a frequently reported adverse effect of statins, and it has been hypothesised that a reduced endogenous coenzyme Q10 concentration is a cause of statin-induced myopathy. Coenzyme Q10 supplementation has therefore been proposed to reduce the adverse muscular effects sometimes seen with statins. Here, we consider whether coenzyme Q10 has a place in the management of statin-induced myopathy.

Palmiwon attenuates hepatic lipid accumulation and hyperlipidemia in a menopausal rat model.

OBJECTIVE: We examined the phytoestrogenic effects of palmiwon on breast carcinoma, lipid accumulation in methyl-ß-cyclodextrin-induced HepG2 cells, and lipid-related diseases in a rat model of menopausal hyperlipidemia. METHODS: E-Screen assay was used to screen for phytoestrogens, especially those with antiestrogenic activity, in MCF-7 cells. Oil Red O staining and intracellular cholesterol analyses were used to quantify cellular cholesterol levels. 3-Hydroxy-3-methyl glutaryl coenzyme A reductase assay was used to measure enzyme activity. The levels of phosphorylated adenosine monophosphate-activated protein kinases and products of genes involved in cholesterol synthesis were measured by Western blot analysis. Thirty rats were either ovariectomized or sham-operated and randomly assigned to four groups (n = 5)-Sham, OVX, OVX-SV, or OVX-PMW (50, 150, or 450 mg/kg) group-for 8 weeks. A number of targets associated with lipid-related diseases were examined to confirm the estrogenic effects of palmiwon. RESULTS: Palmiwon showed antiestrogenic activity in MCF-7 cells. Palmiwon decreased lipid accumulation, total cholesterol levels, and low-density lipoprotein/very-low-density lipoprotein levels in HepG2 cells. Moreover, palmiwon reversed the effects of methyl-ß-cyclodextrin on cholesterol synthesis regulators and inhibited the activity of 3-hydroxy-3-methyl glutaryl coenzyme A reductase. Phosphorylation of adenosine monophosphate-activated protein kinase was stimulated by palmiwon. In ovariectomized rats, palmiwon reduced retroperitoneal and perirenal fat accumulation, serum lipids, atherogenic index, cardiac risk factor score, intima-media thickness, and nonalcoholic steatohepatitis scores. CONCLUSIONS: These results indicate that palmiwon inhibits lipid accumulation without estrogenic activity in the breast. Therefore, palmiwon may have potential as a therapeutic agent for the treatment of hyperlipidemia in postmenopausal women.

Mianserin, an antidepressant kills Leishmania donovani by depleting ergosterol levels.

In the present study, we have investigated the antileishmanial potential of mianserin, an antidepressant. Mianserin was found to inhibit both the promastigote and amastigote forms of the parasite in a dose dependant manner. The IC50 values for promastigotes and amastigotes were 21 µM and 46 µM respectively. Interestingly, mianserin failed to inhibit THP-1 differentiated macrophages up to 100 µM concentration thus, exhibiting parasite selectivity. When mianserin was incubated with recombinant Leishmania donovani 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme, it exhibited an IC50 value of 19.8 µM. Inhibition kinetics revealed competitive mode of enzyme inhibition as the Km increased with no change in Vmax. Further structural investigation of enzyme-inhibitor interaction revealed quenching of HMGR tryptophan intrinsic fluorescence with a K(sv) value of 3.025±0.37 M(-1) and an apparent binding constant of 0.0954 mM. We further estimated ergosterol levels which is a major component of Leishmania cell membrane. It is synthesized by HMGR enzyme, the first rate limiting enzyme of the sterol biosynthetic pathway. Analysis of ergosterol levels by HPLC revealed ∼2.5-fold depletion in mianserin treated promastigotes with respect to untreated parasites. This data was further validated by exogenous supplementation of mianserin treated cells with ergosterol and cholesterol. Reversal of growth inhibition was observed only upon ergosterol addition though it was refractory to cholesterol supplementation. Overall, our results demonstrate the possibility of repositioning of an antidepressant for the treatment of Visceral Leishmaniasis.

The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: a proposal as a therapeutic target and as a study model.

The enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzes the conversion of HMG-Co-A into mevalonate. This step is the limiting point for the synthesis of cholesterol in mammals and ergosterol in fungi. We describe in this article the genome organization of HMGR coding genes and those deduced from different fungi, recount the evidence showing statins as HMGR inhibitors for ergosterol synthesis and its effect in yeast viability, and propose fungal HMGR (HMGRf) as a model to study the use of pharmaceutical compounds to inhibit cholesterol and ergosterol synthesis. Bibliographical search and bioinformatic analyses were performed and discussed. HMGRfs belong to the class I with a high homology in the catalytic region. The sterol biosynthetic pathway in humans and fungi share many enzymes in the initial steps (such as the HMGR enzyme), but in the last steps enzymes are different rendering the two final products: cholesterol in mammals and ergosterol in fungi. With regards to inhibitors such as statins and other compounds, these affect also fungal viability. Since HMGR from Schizosaccharomyces pombe and Ustilago maydis are very similar to the human HMGR in the catalytic regions, we propose that fungal enzymes can be used to test inhibitors for a potential use in humans. We consider that HMGRf is a good therapeutic target to design and test new antifungal compounds. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012).

Spermatotoxic effects of Cananga odorata (Lam): a comparison with gossypol.

OBJECTIVE: To compare the antifertility effects of 50% ethanolic extract of the root bark of Cananga odorata with gossypol. DESIGN: Controlled research laboratory study. SETTING: University research laboratory. ANIMAL(S): Male albino rats (Sprague Dawley, body weight 150 +/- 5 g) bred in university animal house. INTERVENTION(S): A 50% ethanolic extract of the root bark of Cananga odorata and gossypol was administered orally for 60 days. On day 61, one third of the animals in each group were killed for various analyses. One half of the remaining animals were used for the evaluation of fertility index, and other half was maintained for 15 days more on normal diet. MAIN OUTCOME MEASURE(S): The epididymal sperm motility, morphology, and count, the testicular activities of HMG CoA reductase, 3beta-hydroxy steroid dehydrogenase, glucose-6-phosphate dehydrogenase, and testicular cholesterol and serum testosterone were assessed. RESULT(S): Differences were not observed in the sperm count and fertility index of the gossypol group in comparison with the C odorata group. But statistically significant alterations were noted in the sperm morphology as well as in the activity of HMG CoA reductase, 3beta-hydroxy steroid dehydrogenase, glucose-6-phosphate dehydrogenase, cholesterol, and protein of the testis and in serum testosterone. On withdrawal of the drugs, sperms in C odorata group became completely motile but not in the gossypol group. The active component is a 52 kd protein. CONCLUSION(S): The ethanolic extract of Cananga odorata possesses antifertility effects.

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitory effect of Vitis vinifera.

Activity-guided fractionation of the methanol extract of Vitis vinifera bark led to the isolation of epsilon-viniferin, ampelopcin A, vitisin A and vitisin B. Vitisin A and vitisin B showed a remarkable inhibitory activity against 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase with IC50 value of 42.1 microM and 23.9 microM, respectively.

Synthesis and HMG CoA reductase inhibition of 4-thiophenyl quinolines as potential hypocholesterolemic agents.

A series of novel 4-thiophenyl quinoline-based mevalonolactone derivatives were synthesized from ethyl 6,7,8-trisubstituted-4-chloro-quinoline-3-carboxylates by several reactions and evaluated for their ability to inhibit the rat HMG CoA reductase in vitro. It was found that substitution with a variety of thiophenyl groups at position 4 in quinoline resulted in retention or enhancement of the inhibition and the preferable groups were 4-isopropyl-thiophenyl and 3-methoxy-thiophenyl. (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-isopropylthiophenyl-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A16) and (4R, 6S)-6-[(E)-2-(6-fluoro-4,7-di-(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A23) were approximately three times more potent than rosuvastatin or pitavastatin in inhibiting HMG CoA reductase and selected as the hypocholesterolemic candidates for further evaluation.

Effects of trans-10,cis-12 conjugated linoleic acid on cholesterol metabolism in hypercholesterolaemic hamsters.

BACKGROUND: Conjugated linoleic acid (CLA) has received great attention in recent years because of its pleiotropic biological activities, but considerably fewer studies have been published addressing its role in serum lipids and atherosclerosis compared to other topics covered. AIMS OF THE STUDY: The aim of the present study was to assess the effects of the trans-10,cis-12 isomer of CLA on cholesterolaemia and on several metabolic pathways involved in cholesterol metabolism in hamsters. METHODS: Animals were fed atherogenic diets supplemented with 0.5% linoleic acid, 0.5% trans-10,cis-12 CLA or 1.0% trans-10,cis-12 CLA, for 6 weeks. Serum lipoproteins were separated by FPLC. Cholesterol in serum and liver, as well as triacylglycerols and phospholipids in liver were assessed by spectrophotometry. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR), acyl-coenzyme A:cholesterol acyltransferase (ACAT) and cholesteryl ester hydrolase (CEH) activities were measured by radiometry, and LDL receptors were determined by Western blot. RESULTS: trans-10,cis-12 CLA feeding did not modify food intake nor final body weight. Although serum total cholesterol remained unchanged, when cholesterol fractions were analyzed a significant decrease in VLDL-cholesterol was observed in CLA-fed animals, without changes in HDL-cholesterol or LDL-cholesterol. trans-10,cis-12 CLA decreased cholesterol ester content and increased free cholesterol in liver. The activity of HMGCoAR was not modified. In contrast, ACAT activity was reduced by both CLA doses and CEH was increased by the high CLA dose. LDL receptors were significantly reduced by trans-10,cis-12 feeding when expressed as arbitrary units per mg of protein, however, the total receptor mass remained unchanged. CONCLUSIONS: These results suggest that, under the present experimental conditions, trans-10,cis-12 CLA feeding reduces cholesterol esterification in liver and decreases the minority serum VLDL-cholesterol fraction, but it does not show a hypocholesterolaemic effect. A dose-response effect was not observed.

Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase blunts factor VIIa/tissue factor and prothrombinase activities via effects on membrane phosphatidylserine.

OBJECTIVE: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) exhibit antithrombotic properties that are independent of reductions in circulating LDL cholesterol. We hypothesized that these antithrombotic properties are mediated by membrane alterations secondary to disrupted lipid metabolism. METHODS AND RESULTS: EA.hy926 cells were incubated in the presence of 1 micromol/L atorvastatin supplemented with fetal bovine serum or lipid-depleted serum mixtures. Lipid restriction alone had no effect on cell lipid composition but when atorvastatin was included, phosphatidylserine, sphingomyelin, and cholesterol were reduced by 50% while ceramide content decreased by 70%. These changes in lipid composition did not alter the association of decay accelerating factor or tissue factor with lipid rafts. Atorvastatin in combination with lipid restriction reduced factor VIIa/tissue factor activity by as much as 75% but did not alter tissue factor expression. Prothrombinase activity was reduced to an extent similar to factor VIIa/tissue factor. Mevalonic acid but not LDL reversed the observed changes in lipid content and prothrombinase activity induced by atorvastatin. These findings were confirmed in primary cells. CONCLUSIONS: Inhibition of HMG-CoA reductase limits exposure of phosphatidylserine at the cell surface by restricting the cellular pool of mevalonate-derived isoprenoids. This membrane alteration restricts the activity of proteolytic enzyme complexes that propagate the coagulation cascade.

Spray-dried milk supplemented with alpha-linolenic acid or eicosapentaenoic acid and docosahexaenoic acid decreases HMG Co A reductase activity and increases biliary secretion of lipids in rats.

In our earlier study, we have shown that rats fed spray-dried milk containing alpha-linolenic acid (LNA 18:3 n-3) or eicosapentaenoic acid (EPA 20:5 n-3) and docosahexaenoic acid (DHA 22:6 n-3) had significantly lower amounts of serum and liver cholesterol. To evaluate the mechanism for hypocholesterolemic effect of n-3 fatty acids containing milk formulation, we fed male Wistar rats with spray-dried milk containing linseed oil (LSO) (source of LNA) or fish oil (FO) (source of EPA+DHA) for 8 weeks. Feeding n-3 fatty acid containing milk formulation lowered the hepatic 3-hydroxy-methylglutaryl coenzyme A (HMG Co A) activity by 17-22% compared to rats given control diet devoid of n-3 fatty acids. The cholesterol level in liver microsomes was found to be decreased by 16% and 20%, respectively, in LSO and FO containing formulation fed rats. The bile flow was enhanced to an extent of 19-23% in experimental groups compared to control animals. The biliary cholesterol and phospholipid secretion was increased to an extent of 49-55% and 140-146%, respectively, in rats fed n-3 fatty acid containing formulation. The increase in the total bile acids secretion in bile was mainly reflected on an increase in the levels of taurine conjugated bile acids. These results indicated that n-3 fatty acid containing spray-dried milk formulation would bring about the hypocholesterolemic effect by lowering HMG Co A reductase activity in liver and by increasing the secretion of bile constituents.

Hypocholesterolemic effect of physically refined rice bran oil: studies of cholesterol metabolism and early atherosclerosis in hypercholesterolemic hamsters.

Physically refined rice bran oil containing 2-4% nontriglyceride components as compared to other vegetable oils appears to be associated with lipid lowering and antiinflammatory properties in several rodent, primate and human models. These experiments were designed to investigate possible mechanisms for the hypocholesterolemic effect of the physically refined rice bran oil and to examine its effect on aortic fatty streak formation. In the first experiment, 30 hamsters were fed, for 8 weeks, chow-based diets plus 0.03% added cholesterol and 5% (wt/wt) coconut, canola, or physically refined rice bran oil (COCO, CANOLA or PRBO animal groups, respectively). Both plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly reduced in PRBO but not in CANOLA relative to COCO. PRBO also showed a significant 15-17% reduction in cholesterol absorption and significant 30% increase in neutral sterol (NS) excretion with no effect on bile acid (BA) excretion. Both CANOLA and PRBO showed a significant 300-500% increase in intestinal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and significant (>25%) decrease in hepatic HMG-CoA reductase activities with respect to COCO. In a second experiment, 36 hamsters were fed chow-based diets with 0.05% added cholesterol, 10% coconut oil and 4% additional COCO, CANOLA or PRBO. Relative to COCO and CANOLA, plasma TC and LDL-C were significantly reduced in PRBO. Early atherosclerosis (fatty streak formation) was significantly reduced (48%) only in PRBO, relative to the other two. These results suggest that the lipid lowering found in PRBO is associated with decreased cholesterol absorption, but not hepatic cholesterol synthesis, and that the decrease in fatty streak formation with this oil may be associated with its nontriglyceride components not present in the other two diets.

Regulation of HMG-CoA reductase in MCF-7 cells by genistein, EPA, and DHA, alone and in combination with mevastatin.

We investigated the regulation of HMG-CoA reductase in MCF-7 human breast cancer cells by genistein, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). All three compounds down-regulated reductase activity, primarily through post-transcriptional effects. In mevastatin-treated cells, only genistein and DHA abrogated the induction of reductase activity caused by this competitive inhibitor. Diets rich in soy isoflavones and fish oils, therefore, may exert anti-cancer effects through the inhibition of mevalonate synthesis in the breast. Genistein and DHA, in particular, may augment the efficacy of statins, increasing the potential for use of these drugs in adjuvant therapy for breast cancer.

4-hydroxycinnamate lowers plasma and hepatic lipids without changing antioxidant enzyme activities.

BACKGROUND/AIMS: The purpose of this study was to investigate the influence of 4-hydroxycinnamate (4-(OH)-C) supplement on the lipid metabolism and antioxidant system of rats fed a high-cholesterol diet. METHODS: Three groups of rats were given a diet containing 1 g cholesterol/kg for 6 weeks. The control group only received a high cholesterol diet, whereas the other two groups received a diet including lovastatin or 4-(OH)-C (0.1 g/100 g). RESULTS: The plasma total cholesterol concentration was significantly lowered by the 4-(OH)-C supplement, whereas the HDL-cholesterol level was higher in this group. The 4-(OH)-C supplement significantly lowered the hepatic cholesterol and triglycerides levels, respectively. Accumulation of hepatic lipid droplet was the highest in control group; however, it was decreased by supplementation of the 4-(OH)-C and the lovastatin. The hepatic HMG-CoA reductase activities were not significantly different between the groups, whereas the ACAT activity was significantly lowered in the lovastatin group. The 4-(OH)-C significantly lowered the hepatic TBARS content. And it did not alter the neutral sterol and total fecal sterol, however, the fecal acidic sterol was higher in the lovastatin and the 4-(OH)-C groups than in the control group. CONCLUSION: These results indicate that 4-(OH)-C was effective in lowering the plasma cholesterol and hepatic lipids.

Inhibition of both the apical sodium-dependent bile acid transporter and HMG-CoA reductase markedly enhances the clearance of LDL apoB.

Discovery of the ileal apical sodium-dependent bile acid transporter (ASBT) permitted development of specific inhibitors of bile acid reabsorption, potentially a new class of cholesterol-lowering agents. In the present study, we tested the hypothesis that combining the novel ASBT inhibitor, SC-435, with the HMG-CoA reductase inhibitor, atorvastatin, would potentiate reductions in LDL cholesterol (LDL-C) and LDL apolipoprotein B (apoB). ApoB kinetic studies were performed in miniature pigs fed a typical human diet and treated with the combination of SC-435 (5 mg/kg/day) plus atorvastatin (3 mg/kg/day) (SC-435+A) or a placebo. SC-435+A decreased plasma total cholesterol by 23% and LDL-C by 40%. Multicompartmental analysis (SAAM II) demonstrated that LDL apoB significantly decreased by 35% due primarily to a 45% increase in the LDL apoB fractional catabolic rate (FCR). SC-435+A significantly decreased hepatic concentrations of free cholesterol and cholesteryl ester, and increased hepatic LDL receptor mRNA consequent to increased cholesterol 7alpha-hydroxylase expression and activity. In comparison, SC-435 (10 mg/kg/day) monotherapy decreased LDL apoB by 10% due entirely to an 18% increase in LDL apoB FCR, whereas atorvastatin monotherapy (3 mg/kg/day) decreased LDL apoB by 30% due primarily to a 22% reduction in LDL apoB production. We conclude that SC-435+A potentiates the reduction of LDL-C and LDL apoB due to complementary mechanisms of action.