INTRODUCTION:

Cholesterol is a waxy, fat-like substance that performs the similar functions in humans and animals as phytosterols in plants. Cholesterol is either synthesized de novo in liver, or taken up from the diet. This organic chemical substance plays an important role in body metabolism and membrane transport. It is essential for the maintenance of membrane fluidity over the range of temperature; and also acts as a precursor for synthesis of steroid hormones, bile acids and vitamin D.¹ Cholesterol is synthesized in liver from acetyl-Co-A in a complex biosynthetic pathway, where the rate limiting step is the conversion of HMG-Co-A to mevalonate catalyzed by the enzyme HMG-Co-A reductase (HMGR). LDL or “bad cholesterol” is responsible for the building up cholesterol inside the artery walls. Alternatively, HDL or “good cholesterol” helps in removal of cholesterol from the blood and prevents arterial wall build up. Imbalanced cholesterol levels are found to be associated to various physiological conditions like CVDs and dyslipidemia.²

Drugs that inhibit HMGR, known as HMG-CoA reductase inhibitors (or "statins"), are the first line drugs to control plasma cholesterol. Statins are natural compounds of fungal origin that are produced as secondary metabolites. They are bulky and literally get “stuck” in the active site of HMGR and prevent the enzyme from binding with its substrate, HMG-CoA, thus block the mevalonate pathway of cholesterol synthesis.³ With the emerging multiple therapeutic effects which are beyond just lipid lowering, these wonder drugs “statins” are proving to be much more powerful drugs than ever thought.

Hypercholesterolemia

Hypercholesterolemia is the presence of high levels of cholesterol in the blood. The abnormal build up of cholesterol forms clumps (plaque) that narrows and hardens the artery walls. As the clumps get bigger, they can clog the arteries and restrict the flow of blood. Over time, the plaque can cause narrowing of arteries. This plaque buildup is called atherosclerosis. This build up of plaque in coronary arteries causes a form of chest pain called angina and greatly increases a person's risk of having a heart attack.^4,5 Abnormal cholesterol levels lead to angina, coronary heart disease, heart arrhythmias -- an irregular heart rhythm, transient ischemic attack (TIA, or "mini" stroke), heart attack, stroke, peripheral artery disease, high blood pressure etc. The effects of high cholesterol will depend on whether the atherosclerosis partially or completely blocks the artery.⁵ Inherited forms of hypercholesterolemia can also cause health problems related to the buildup of excess cholesterol in other tissues. If cholesterol accumulates in tendons, it causes characteristic growths called tendon xanthomas. These growths most often affect the achilles tendons and tendons in the hands and fingers. Yellowish cholesterol deposits under the skin of the eyelids are known as xanthelasmata.⁶ Cholesterol can also accumulate at the edges of the clear, front surface of the eye (the cornea), leading to a gray-colored ring called an arcus cornealis.⁷

Blood test called lipoprotein profile is used to diagnose the cholesterol levels in the blood. Lipoprotein profile gives the information about total cholesterol, LDL, HDL and triglycerides. Having high cholesterol levels, does not itself present any signs or symptoms. Unless routinely screened through regular blood testing, high cholesterol levels will go unnoticed and could present a silent threat of heart attack or stroke. Doctors' guidelines state that everyone over the age of 20 years should have their cholesterol levels checked once every five years. The cholesterol test is done after a period of fasting - no food, drink or pills for 9 to 12 hours - to enable an accurate reading of cholesterol from the blood test. The screening gives information about total cholesterol (TC), HDL cholesterol, LDL cholesterol and triglyceride (TG) levels. The guidelines set cholesterol levels are as follows in table 1 (Adult Treatment Panel (III) Final Report, 2002).⁸

Table 1: ATP III Classification of LDL, total, and HDL Cholesterol (mg/dL)

S.No	LDL cholesterol
1	Optimal	<100 mg/dL
2	Near-optimal	100 to 129 mg/dL
3	Borderline high	130 to 159 mg/dL
4	High	160 to 189 mg/dL
5	Very high	≥190 mg/dL
	Total cholesterol (TC)
1	Desirable	<200 mg/dL
2	Borderline high	200-239 mg/dL
3	High	≥240 mg/dL
	HDL cholesterol
1	Low	<40 mg/dL
2	High	> 60 mg/dL
	Triglycerides (TG)
1	Normal	<150 mg/dL
2	Borderline High	150-199 mg/dL
3	High	200-499 mg/dL
4	Very High	500 mg/dL

Treatment of hypercholesterolemia

High cholesterol levels can be managed with lifestyle changes, medications, or a combination of these approaches. In certain cases, trial of lifestyle changes like reducing total and saturated fat in the diet, losing weight (if overweight or obese), performing aerobic exercise, and eating a diet rich in fruits and vegetables is recommended before medication. However, the success of lipid lowering with lifestyle modification varies widely. There are several medications available to normalize serum cholesterol levels. Various categories of medications available to regulate cholesterol metabolism are described below.

1. Cholesterol Absorption Inhibitors

Cholesterol absorption inhibitors lower cholesterol by preventing it from being absorbed in the intestine. The first approved drug in this class, Zetia (ezetimibe), was launched in 2002. It localizes at the brush border of the small intestine and inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides, or bile acids. Side effects include headache, nausea and muscle weakness.^{9, 10}

2. Fibric acid derivatives

Fibric acid derivatives, or fibrates, affect the actions of key enzymes in the liver, enabling the liver to absorb more fatty acids, thus reducing production of triglycerides. These drugs also work well at increasing production of HDL. They lower LDL levels by 10 -15 percent, increase HDL levels by 5-20 percent, and lower triglycerides by 20-50 percent. Atromid-S (clofibrate), Lopid (gemfibrozil), and Tricor (fenofibrate) are the commonly available fibrates in the market. However fibrates can cause side effects like myositis, stomach upset, sun sensitivity, gallstones, irregular heartbeat, and liver damage.^{11, 12}

3. Bile acid sequestrants

Bile acid sequestrants are in use for more than 40 years with no major side effects, acts like super glue, binding with bile acids in the intestines so that the acids are removed with the stool. Bile acids are made from cholesterol in the liver. As they pass through the intestines they are reabsorbed into the bloodstream and carried back to the liver. This “recycles” the cholesterol component as well. But bile acid sequestrants interrupt this pathway, causing the bile acids to exit the body. This causes a loss of cholesterol as well. The most common drugs include cholestyramine, sold under the brand names Questran, Prevalite, and LoCholest, and colestipol (Colestid). These drugs generally lower LDL about 15 to 30 percent with relatively low doses while increasing HDL slightly (up to 5 percent). Common side effects include bloating, constipation, heartburn, and elevated triglycerides.^{13, 14}

4. Statins

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) and the most effective class of drugs to treat hypercholesterolemia. Statins interfere in the cholesterol biosynthesis by inhibiting the conversion of HMG-CoA into mevalonate. This inhibition leads to a decrease in the total cholesterol. The essential structural components of all statins are dihydroxyheptanoic acid unit and a ring system with different substituent (Figure 1). The statin pharmacophore is modified hydroxyglutaric acid component, which is structurally similar to the endogenous substrate HMG CoA. The orientation and bonding interactions of the HMG moieties of the inhibitors clearly resemble those of the substrate complex. Thus, statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site ^{15, 16}. Six statins approved by U.S. Food and Drug Association (FDA) are available for lowering cholesterol (Lovastatin – Mevacor, Pravastatin – Pravachol, Simvastatin – Zocor, Atorvastatin- Lipitor, Fluvastatin – Lescol, Rosuvastatin - Crestor).

1(a) Base structure of statins (naphthalene ring and

β-hydroxylactone)

1(b) Statin side chains (substituents) linked at C8 (R1) and C6 (R2) of the base structure

Figure 1: Structure of statins (Adapted from (Manzoni and Rollini 2002)³

These statins are classified in two groups:

Type 1 statins : This class of statins are naturally produced and have substituted decalin-ring structure that resemble the first statin ever discovered, mevastatin have often been classified as type 1 statins due to their structural relationship. Statins that belong to this group are: Lovastatin, Pravastatin, and Simvastatin ¹⁷.

Type 2 statins: This class of statins is synthetic in nature and the main differences between the type 1 and type 2 statins is the replacement of the butyryl group of type 1 statins by the fluorophenyl group of type 2 statins. This group is responsible for additional polar interactions that cause tighter binding to the HMGR enzyme. Statins that belong to this group are: Fluvastatin, Atorvastatin, and Rosuvastatin.¹⁷

Table 2: Brief history of statins discovery and development:

Year	Major Discovery
Mid-1970s	The cholesterol controversy, Phase 1, which lasted until 1984. Discovery of compactin, the first potent inhibitor of cholesterol synthesis.
1978	Discovery of lovastatin.
1980	Lovastatin shown to be effective in healthy volunteers in early clinical trials; compactin withdrawn from clinical trials, causing suspension of further trials.
1984	Clinical trials with lovastatin resume.
1987	Lovastatin becomes available for prescription, first of the class.
1994	Unequivocal reduction of mortality with simvastatin in 4S trial resolves the cholesterol controversy.
1995-1998	Four five-year clinical outcome trials with pravastatin and lovastatin all show reduction of coronary events with very few adverse effects.
2001	Withdrawal of cerivastatin due to excessive risk of rhabdomyolysis.
2002	Heart Protection Study confirms safety of simvastatin in five-year trial in 20,000 patients and demonstrates clinical benefit in a broad array of patient types, including those with low cholesterol levels.
2003	The statin Crestor (rosuvastatin) was approved by the FDA in 2003 for use in treating high cholesterol.
2006	The U.S. Food and Drug Administration approved generic Pravastatin.
2007	Statin use prevent gallstones forming, particularly in women who have diabetes.
2009	FDA approval for Pitavastatin.
2010	Rosuvastatin was approved by the FDA for the primary prevention of cardiovascular events.
2011	Sitagliptin and Simvastatin combination - Juvisync - approved by FDA for diabetes with high cholesterol.
2012	Statins Tied To Reduced Cancer Deaths.
2013	Liptruzet (ezetimibe and atorvastatin) approved by FDA to cut cholesterol, despite criticism by cardiologists.

Natural Statins

During evolution, some fungi such as mushrooms developed a defence mechanism in which they produce statins that blocks the biosynthesis of cholesterol. Since bacteria require cholesterol-like compounds to grow, statins could fend off invading bacteria by shifting the bacteria’s ability to generate these compounds. So statins were produced by fungus as a part of their defence mechanism. The microorganisms used for statin production broadly belongs to three main groups, Aspergillus, Penicillium and Monascus spp. (Table 1). The initial studies were carried out mainly with P. brevicompactum, P. citrinum, and A. terreus. The recent studies under submerged fermentation conditions have been mostly performed with A. terreus. This study is explored in industry to produce drug with various name using following micro-organisms in different mode of fermentation:

Table 3: Statin production using fermentation (2003-2013)

S.No	Organism	Mode of production	Product	Reference
1	A. terreus	Submerged fermentation	Lovastatin	Casas lopez et al. ¹⁸
2	P. citrinum		Compactin	Choi et al. ¹⁹
3	M. pilosus		Lovastatin	Miyake et al.²⁰
4	P. citrinum		Compactin	Zaffer Ahmad et al.²¹
5	A. terreus		Lovastatin	Rodriguez Porcel et al. ²²
6	A. terreus		Lovastatin	Gupta et al. ²³
7	P.brevicompactum		Mevastatin	M.Manzoni et al.³
8	M. purpureus		Lovastatin	Sayyad et al.²⁴
9	A. terreus		Lovastatin	Jia et al.²⁵
10	A. terreus		Lovastatin	Kaur et al.²⁶
11	A.terreus		Lovastatin	Sorrentino et al.²⁷
12	M. purpureus		Lovastatin	Subhagar et al. ²⁸
13	A. terreus		Lovastatin	Li et al.²⁹
14	A. terreus		Lovastatin	Li et al.
15	M. oryzae		Lovastatin	Ahmed I.El-Batal et al.³⁰
16	Amycolatopsis sp		Wuxistatin	Hui et al.³¹
17	A. macra		Pravastatin	Ajaz Ahmad et al.³²
18	A. livida		Pravastatin
19	A. madurae		Pravastatin
20	Streptomyces sp.		Pravastatin	Park JW et al.³³
21	A. flavipes	Solid State fermentation	Lovastatin	Valera et al. ³⁴
22	M. ruber		Lovastatin	Xu et al. ³⁵
23	P.brevicompactum		Compactin	Shaligram et al.³⁶
24	A. terreus		Lovastatin	Banos et al. ³⁷
25	M. purpureus		Compactin	Panda et al.³⁸
26	M. purpureus		Lovastatin	Subhagar et al.³⁹
27	M. pilosus		Lovastatin	Tsukahara et al.⁴⁰
28	A. terreus		Compactin	Pansuriya and Singhal ⁴¹
29	M. purpureus		Lovastatin	Panda et al.⁴²
30	A. terreus		Lovastatin	Patil et al.⁴³
31	A. terreus		Lovastatin	Jahromi et al.⁴⁴
32	A. terreus		Lovastatin	Pei-lian et al. ⁴⁵
33	A. tubingensis		Lovastatin	Zhen-Jun Zhao et al. ⁴⁶
34	A. wentii		Lovastatin
35	A. fumigates		Lovastatin
36	P. chrysogenum		Lovastatin
37	T. asperellum		Lovastatin
38	T. citrinoviride		Lovastatin

Table 4: Multiple therapeutic applications of statins

S.No	Disease	Possible underlying mechanism	Author/Year
1	Cholesterol Lowering	Inhibits the mevalonate pathway by blocking the rate limiting step of pathway via inhibiting HMGR	(Goldstein and Brown 1990) ⁴⁹
2	Cardiovascular Disease (CVD)	Plaque stabilization, improvements in endothelial-mediated responses with better local regulation of the coronary arterial tone and an immunosuppressive effect.	(Brown et al. 1993; Anderson et al. 1995) ^50,51
3	Anti Inflammatory and Anti oxidant	Reduce the plasma levels of inflammatory markers like CRP due to an inhibition of IL-6 in the vascular tissues. Inhibit the ability of macrophages to oxidise LDL.	(Giroux, Davignon,and Naruszewicz 1993) ⁵²
4	Bone Regeneration	Promote osteoblastic and inhibit osteoclastic activity.	(Park 2009) ⁵³
5	Cancer	Simvastatin on LNCaP and PC3 cells showed its ability to inhibit serum-stimulated Akt activity and reduced expression of PSA. Akin to this, inhibited serum-induced cell migration, invasion, colony formation, and proliferation.	(Kochuparambil et al. 2011) ⁵⁴
6	Alzheimer’s Disease (AD)	Modulation of amyloid-precursor protein (APP) cleavage by altering membrane cholesterol levels in vitro. It completely rescued cerebrovascular reactivity, basal endothelial nitric oxide synthesis, and activity-induced neuro metabolic and neurovascular coupling.	(Eckert, Wood, and Müller 2005; Tong et al. 2012) ^55,56
7	Parkinson’s Disease	Simvastatin exposure inhibited the activation of p21ras (necessary for the neurotoxic chemical to produce Parkinson's) in the microglial cells. The statin also blocked the neurotoxin from activating nuclear factor-kappa B, "a transcription factor required for the transcription of most of the pro inflammatory molecules.	(Ghosh et al. 2009) ⁵⁷
8	Infectious Diseases	Improved susceptibility to endothelial nitric oxide synthase stimulation and reduced endothelial adhesion of leukocytes, results in improved survival after sepsis.	(Merx et al. 2005) ⁵⁸
9	Renal Diseases	Slow progression of chronic kidney diseases by improving the lipid profile as well as by affecting inflammatory cell-signalling pathways that control vascular cell migration, proliferation, and differentiation.	(Campese and Park 2007) ⁵⁹
10	Acute Lung Injury (ALI)	Vascular-protective changes in EC phenotype can be attributed to statin-induced inhibition of mevalonate production and the resultant changes in Rho GTPase activity and localization	(Singla and Jacobson 2012) ⁶⁰
11	Rheumatoid Arthritis (RA)	Adjuvant therapy associated with other conventional therapeutic methods used in RA. Statins improve endothelial function in patients with RA. Its beneficial effect may be attributed to lowering pro-inflammatory CRP and TNF-alpha concentrations.	(Tikiz et al. 2005) ⁶¹
12	Aging	By telomerase activation, statins may represent a new molecular switch able to slow down senescent cells in tissues and be able to lead healthy lifespan extension.	(Boccardi et al. 2013) ⁶²
13	Cognitive disorders	Due to their cholesterol-lowering effects, increase of soluble RAGE level by inducing RAGE (receptor for advanced glycation end products) shedding occurs, and by this way, might prevent the development of RAGE-mediated pathogenesis.	(Quade-Lyssy et al. 2013) ⁶³
14	Pancreatic Diseases	Use of statin therapy was associated with a lower risk of pancreatitis in patients with normal or mildly elevated triglyceride levels.	(Preiss et al. 2012) ⁶⁴
15	Pregnancy Complications	Prevent preeclampsia by decreased release of the anti-angiogenic molecule sFlt-1 from macrophages and increased release of VEGF and PlGF to restore angiogenic balance.	(Girardi 2013) ⁶⁵
16	Healing Disorders	Decreasing farnesyl pyrophosphate, facilitating vascular relaxation, promoting neovascularization and reducing bacterial load.	(Stojadinovic et al. 2010) ⁶⁶
17.	Multiple sclerosis	Attributed to the immunomodulatory properties of statins and to their induction of a bias toward Th2 cell anti-inflammatory cytokine production.	(Davignon and Leiter 2005) ⁶⁷

CONCLUSION:

The application of statins has led to a significant reduction in mortalities associated with cardiovascular diseases and dyslipidemia. The statins are known to possess anti-inflammatory properties independent of their lipid-lowering effects, suggesting that as a drug class, they are likely to have a longer shelf life. Hence, focussed efforts are required towards the development of statins with significantly reduced side effects. Furthermore, identification of statins which are at par with their synthetic homologues in terms of cost economics and bio-efficacy may further boost the biotechnological production approach.

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Received on 29.05.2014 Modified on 07.06.2014

Research J. Pharm. and Tech. 7(10): Oct. 2014 Page 1201-1207

Statins: A Review of Wonder Drug from Fungus