Molecular and cellular pharmacologyPromising therapeutic potential of pterostilbene and its mechanistic insight based on preclinical evidence
Introduction
Pterostilbene (PS), or 3,5-dimethoxy-4′-hydroxystilbene (molecular weight: 256.3), is a phytoalexin (Langcake and Pryce, 1977) and naturally derived non-flavonoid polyphenol compound with a structure similar to that of resveratrol (3,5,4′-trihydroxystilbene) (Table 1). PS is a lipid soluble compound that exists in cis and trans forms, with the trans form being most abundant. It was first isolated in 1940 from heartwood of red sandalwood (Pterocarpus santalinus) (Seshadri, 1972) and later identified in grapevines (Vitis vinifera) (Adrian et al., 2000, Langcake et al., 1979, Langcake and Pryce, 1977) and blueberries (Rimando et al., 2004). Interestingly, PS was identified as the major phenolic compound in the wood of Indian kino (Pterocarpus marsupium), and drakshasava has been used by Ayurvedic practitioners in the treatment of diabetes (Manickam et al., 1997), cardiovascular and related problems (Paul et al., 1999) since ancient times. In 2002, Rimando and colleagues reported that PS acts as a cancer chemo-preventive agent, due to its ability to scavenge peroxyl radicals (ROO·) (Rimando et al., 2002). Research interest in PS increased after 2011, when it was shown to have antiproliferative effects in cultured cells at lower concentrations than resveratrol (McCormack et al., 2011). Meanwhile antiinflammatory (Hougee et al., 2005, Pan et al., 2008a, Remsberg et al., 2008), antiobesity (Rimando et al., 2005) and antioxidant (Amarnath Satheesh and Pari, 2006, Kim et al., 2009, Perecko et al., 2008, Remsberg et al., 2008, Rimando et al., 2002) properties have also been reported. More recently, clinical trials have also been conducted to evaluate the potential of PS in treating or preventing cardiac diseases (Riche et al., 2014a). Therefore, PS has become a highly important natural bioactive phytonutrient with potential therapeutic applications and market prospects.
Pterostilbene is synthesized in plants as a secondary metabolite in response to environmental stress or fungal infections (Pezet and Pont, 1990). It is highly concentrated in the fruits, leaves and heartwood of various plants, including Vitis vinifera (grapevine) (Langcake et al., 1979), Pterocarpus marsupium (known in the vernacular as “Vijaysar” of “Bijasar”) (Maurya et al., 1984), sandalwood (Pterocarpus santalinus) (Seshadri, 1972), fungal infected Chardonnay and Gamay grape berries (Adrian et al., 2000) and in healthy and immature Pinot Noir and Gamay berries (Pezet and Pont, 1988), deer berries (Vaccinium stamineum) (Rimando et al., 2004), rabbit eye blueberries (Vaccinium virgatum) (Rimando et al., 2004), blueberries (Vaccinium myrtillus) (Riviere et al., 2012), peanuts (Arachis hypogaea) (Sobolev et al., 2011), and bubinga (Guibourtia tessmanii) (Fuendjiep et al., 2002). The concentration of PS in various food stuffs is summarized in Table 2. PS can be synthesized in plants using a genetic engineering approach via the coexpression of stilbene synthase and O-methyl transferase (Rimando et al., 2012).
The pharmacokinetic profile of PS and its metabolites has been extensively studied in preclinical species (Kapetanovic et al., 2011, Remsberg et al., 2008, Shao et al., 2010, Yeo et al., 2013). Remsberg et al. also evaluated the pharmacokinetics of trans-PS in jugular vein cannulated rats after i.v. injection of 20 m/kg PS. The area under the curve (AUC) for serum, serum half-life, urine half-life, total clearance and volume of distribution during the terminal exponential phase of drug elimination were 17.5±6.6 mg/h/ml, 1.73±0.78 h, 17.3±5.6 h, 0.960±0.025 L/h/kg and 2.41±1.13 L/kg respectively (Remsberg et al., 2008).
Pterostilbene was found to possess dose–dependent pharmacokinetics (Yeo et al., 2013). A trend towards nonlinearity was observed in both the intravenous and oral pharmacokinetics of PS with increasing doses. Dose escalation led to a decrease in the elimination rate, with an almost two-fold decline in clearance at the intravenous dose of 25 mg/kg (36.4±7.8 ml/min/kg) when compared to 2.5 mg/kg (68.2±9.8 ml/min/kg). This may be due to saturation or partial saturation of PS metabolism (Yeo et al., 2013). Whereas, after oral administration, increasing the dose led to about a two-fold increase in bioavailability (F) and a prolonged mean residence time at the doses of 30 and 60 mg/kg compared to the dose of 15 mg/kg, was due to the combined effects of capacity limited absorption and capacity limited elimination (Yeo et al., 2013). Sublingual delivery of 2.5 mg/kg PS led to rapid absorption and moderate bioavailability (F=25.8±13.1%) (Yeo et al., 2013).
Kapetanovic et al. studied the comparative pharmacokinetic profile of PS and resveratrol in rats following oral administration of these agents for 14 consecutive days at 56 or 168 mg/kg/day and 50 or 150 mg/kg/day, respectively (Kapetanovic et al., 2011). Additionally, two groups of rats were administered 10 mg/kg resveratrol or 11.2 mg/kg PS once intravenously. Following administration of equimolar doses, PS demonstrated markedly higher peak serum concentration and AUC values, and its oral bioavailability (66.9%) was several-fold greater than the oral bioavailability of resveratrol (29.8%) (Kapetanovic et al., 2011). Moreover, the plasma levels of PS metabolites were also greater than those of resveratrol. These significant differences stem from dissimilarities in the absorption and metabolism of the two drugs (Kapetanovic et al., 2011). This study demonstrated that, PS possesses superior pharmacokinetic profile than resveratrol following equimolar dose administration to rats (Table 3).
Pterostilbene is anticipated to have high membrane permeability based on its physicochemical characteristics, including moderate lipophilicity (cLogP =4.1) (Perecko et al., 2008), few hydrogen bond acceptors (Baur and Sinclair, 2006) and donors (Roupe et al., 2006), low polar surface area (38.7°A2), and few rotatable bonds (Remsberg et al., 2008).
One of the major drawbacks associated with PS is its poor aqueous solubility (approximately 21 µg/ml) (Bethune et al., 2011). Different approaches have been applied to enhance the aqueous solubility of the drug. The aqueous solubility was enhanced six-fold for PS when it was cocrystalized with piperazine in a 2:1 stoichiometric molar ratio (Bethune et al., 2011). The approach of using solubility enhancing excipients like 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) also enhanced PS bioavailability. A HP-β-CD PS solution (15 mg/kg, administered p.o.) showed better bioavailability (F =59.2±19.6%) than its counterpart PS suspension (F =15.9±7.8%). Food accelerates bile secretion, which can increase the aqueous solubility of co-administered drugs, thus co-administration of PS with or after a meal maximizes its oral absorption significantly, while fasting substantially attenuates its bioavailability (F <5.5%). Therefore, the differences in the oral pharmacokinetics of PS observed between suspension vs solution and fasted vs nonfasted states, could be attributed to differences in solubility (Yeo et al., 2013).
Pterostilbene exhibited a volume of distribution value (5.3 L/kg) that was greater than total body water (~0.7 L/kg), suggesting extensive tissue distribution (Kapetanovic et al., 2011). Plasma concentrations of phase II metabolites of both resveratrol and PS were also much higher than the concentrations of the respective parent compounds (Kapetanovic et al., 2011). It has been proposed that these metabolites could serve as storage pools for the parent drugs, as has been demonstrated for estrone sulfate (van de Wetering et al., 2009, Walle et al., 2004). The reported enterohepatic recirculation of resveratrol is generally consistent with this hypothesis (Marier et al., 2002). The glucuronidated PS metabolite exhibited an increase in concentration at 1–2 h after oral administration, indicating the possibility of enterohepatic recycling of the metabolite (Remsberg et al., 2008).
Numerous drug metabolizing enzymes are broadly classified into two categories: phase I and phase II enzymes. Phase I enzymes primarily consist of the cytochrome P450 (CYP) superfamily, which are responsible for biotransformation (oxidation, reduction, hydrolysis) of foreign molecules in order to make them less toxic, more polar and facilitate their elimination. In general, these enzymes are constitutively expressed in liver, although the expression can be induced further by drugs. Phase II drug metabolizing enzymes are responsible for biotransformation (conjugation) of xenobiotics, including metabolites of phase I drug metabolism. Conjugating and antioxidant enzymes are mainly involved in the phase II mediated detoxification.
Generally, most polyphenols do not undergo hepatic phase I metabolism because their inherent polyphenolic structures provide resistance to breakdown by CYP enzymes (Asensi et al., 2011, Manach et al., 2004). However, polyphenols can directly undergo phase II metabolism, predominately methylation, glucuronidation and sulfation (Gao and Hu, 2010). Evidence suggests that phase II metabolism, particularly glucuronidation and sulfation, is the chief clearance pathway of PS (Kapetanovic et al., 2011, Remsberg et al., 2008). Moreover, the concentrations of plasma metabolites of PS (both sulfate and glucuronide conjugates) were considerably higher than the plasma concentrations of the parent compound (Kapetanovic et al., 2011). At higher doses, PS exhibits capacity limited elimination as the conjugating enzymes may be saturated or partially saturated (Yeo et al., 2013). In a study conducted by Yeo et al. (2013) PS exhibited a lower elimination rate, five-fold lower clearance and ten-fold longer mean transit time than resveratrol, thereby exhibiting superior metabolic stability than resveratrol. This finding could well be justified by the structural difference between the two compounds (PS contains an extra dimethyl ether group) that bestows a lower susceptibility to conjugation metabolism on PS.
A glucuronidated metabolite of PS was predominantly identified in urine (Remsberg et al., 2008). Pterostilbene is suggested to be excreted predominantly via non-renal elimination pathways (99.78% of total PS excreted), as the fraction excreted in urine was found to be 0.219±0.088% (Remsberg et al., 2008). Later, Shao et al. extensively studied nine urinary metabolites in mice, including PS glucuronide, PS sulfate, mono-demethylated PS, mono-demethylated PS glucuronide, mono-demethylated PS sulfate, mono-hydroxylated PS, mono-hydroxylated PS glucuronide, mono-hydroxylated PS sulfate, and mono-hydroxylated PS glucuronide sulfate, using liquid chromatography/atmospheric pressure chemical ionization and electrospray ionization tandem mass spectrometry (Shao et al., 2010).
Studies performed in vivo and in vitro have shown that PS exerts pleiotropic health effects and can prevent or slow the progression of several pathological conditions, including cardiovascular and metabolic diseases, ischemic brain injuries, and cancer (Amarnath Satheesh and Pari, 2006, Riche et al., 2014a, Rimando et al., 2002, Yang et al., 2015) (Fig. 1). This review attempts to highlight the underlying mechanisms and pathways reflecting the cancer, cerebral and cardiovascular treatment potential of PS, based on the findings of recent studies. The overall aim of this review is to discuss the frontiers in the field of PS’s multifarious mechanisms and health–related use.
Section snippets
PS and cancer
In 2002, Rimando et al. (2002) published the cancer chemopreventive activities of PS for the first time. They demonstrated that, similar to the well-known polyphenol anticancer agent resveratrol (ED50=3.2 µM), PS (ED50=4.8 µM) significantly reduced the 7,12-dimethylbenz[a]anthracene-induced preneoplastic lesions in vitro using mouse mammary culture cells (Jang et al., 1997). Pterostilbene gained research interest only after 2011, when it was demonstrated to have antiproliferative effects in
PS and CNS diseases
Several studies have suggested that the CNS is targeted by PS. Pterostilbene has been shown to exert beneficial effects against CNS diseases by altering several molecular targets (Fig. 3). Andres-Lacueva et al. (2005) suggested that blueberry constituents display beneficial effects on the CNS by permeating through the lipophilic blood brain barrier and modifying CNS signaling. Resveratrol, a PS like compound with lower lipophilicity, is, in fact, able to cross the blood brain barrier (Baur et
Antidiabetic mechanism of PS
Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia with disturbances in carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action or both (Baquer et al., 1998). Recent preclinical and clinical evidence suggests that PS also exerts a strong influence on glucose homeostasis. Pterostilbene has been shown to decreased plasma glucose levels and increased plasma insulin levels significantly in diabetic animals (Amarnath Satheesh
Safety
Recent studies have investigated the safety profile of PS. Most of the data available, both in human and in animal models, suggests that PS does not have significant toxic effects. For example, no toxic effects or mortality were observed in mice given oral supplementation of PS over the dose range of 0, 30, 300, and 3000 mg/kg body weight/day for four weeks (Ruiz et al., 2009). Moreover, PS fed mice showed increased RBC counts and hematocrit relative to control mice. Further, biochemical and
Conclusion
Pterostilbene is a traditional dietary antioxidant that shows multispectral activity with a multifarious mechanism of action. In this review, we have focused our attention on the mechanism of action of PS, in particular as it relates to cancer, brain injury and heart disease. Preclinical research has endorsed the potential anticancer, cerebroprotective, and cardioprotective activities of PS.
Prudent observance of the studies for anticancer activity of PS reveals that high concentrations of PS
Conflict of interest
The authors declare no conflict of interest in this work.
Acknowledgments
The first author is grateful to the Indian Institute of Technology (Banaras Hindu University), Varanasi for providing financial support in the form of Teaching Assistanceship funded by Ministry of Human Resource Development, Government of India.
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