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Journal of Enzyme Inhibition and Medicinal Chemistry Volume 31, 2016 - Issue 6
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Original Article

The effect of caffeic acid phenethyl ester (CAPE) on metabolic enzymes including acetylcholinesterase, butyrylcholinesterase, glutathione S-transferase, lactoperoxidase, and carbonic anhydrase isoenzymes I, II, IX, and XII

İlhami GülçinDepartment of Chemistry, Faculty of Science, Ataturk University, Erzurum, Turkey, ;Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia, Correspondence[email protected]
,
Andrea ScozzafavaDipartimento Di Chimica Ugo Schiff, Università Degli Studi Di Firenze, Firenze, Italy,
,
Claudiu T. SupuranDipartimento Di Chimica Ugo Schiff, Università Degli Studi Di Firenze, Firenze, Italy, ;Department of Neurofarba, Section of Pharmaceutical and Nutriceutical Sciences, Università Degli Studi Di Firenze, Florence, Italy,
,
Hulya AkıncıoğluCentral Researching Laboratory, Agri Ibrahim Cecen University, Agri, Turkey, and
,
Zeynep KoksalDepartment of Chemistry, Faculty of Science, Ataturk University, Erzurum, Turkey,
,
Fikret TurkanHealth Services Vocational School, Igdır University, Igdır, Turkey
&
Saleh AlwaselDepartment of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia,
show all
Pages 1095-1101 | Received 08 Aug 2015, Accepted 11 Sep 2015, Published online: 09 Oct 2015

Abstract

Caffeic acid phenethyl ester (CAPE) is an active component of honeybee propolis extracts. Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread and intensively studied metalloenzymes present in higher vertebrates including humans as many diverse isoforms. Acetylcholinesterase (AChE) is responsible for acetyl choline (ACh) hydrolysis and plays a fundamental role in nerve impulse transmission by terminating the action of the ACh neurotransmitter at cholinergic synapses and neuromuscular junctions. Butyrylcholinesterase (BChE) is another enzyme abundantly present in the liver and released into blood in a soluble form. Lactoperoxidase (LPO) is an enzyme involved in fighting pathogenic microorganisms whereas glutathione S-transferases (GSTs) are dimeric proteins present both in prokaryotic and eukaryotic organisms and involved in cellular detoxification mechanisms. In the present study, the inhibition effect of CAPE on human carbonic anhydrase (hCA) isoforms I, II, IX, and XII, AChE, BChE, LPO, and GST was evaluated. CAPE inhibited these enzymes with Kis in the range between micromolar to picomolar. The best inhibitory effect was observed against AChE and BChE.

Introduction

Polyphenolic compounds derived from natural products are well known to possess a range of biological activities such as antioxidantCitation1, antitumoralCitation2, anti-inflammatory, anti-viral, and immunomodulatory propertiesCitation3,Citation4. Anti-allergicCitation5, anti-carcinogenicCitation6, neuroprotectiveCitation7, anti-atherosclerotic, and anti-free radicals properties were also reported for these derivativesCitation8–11. They incorporate one or more hydroxyl moieties bonded directly to an aromatic carbon atomCitation12–19 with the substitution patterns on the aromatic ring creating a large chemical varietyCitation20–25.

Caffeic acid phenethyl ester (CAPE) is a biologically active ingredient of honeybee propolis. It has the ability to suppress lipid peroxidationCitation26 and is also a potent inhibitor of nuclear factor-kappa β activationCitation27. This naturally bioactive and hydrophobic polyphenolic ester is found in numerous plantsCitation28. CAPE has important biological activities including anti-viralCitation29, anti-inflammatoryCitation30, and antioxidant activitiesCitation14.

Carbonic anhydrases (CAs, EC 4.2.1.1) represent a superfamily of widespread enzymes, which catalyze a crucial biochemical reaction, the reversible hydration of carbon dioxide (CO2) to bicarbonate () and protons (H+)Citation31–37. These enzymes are present in all organisms, from the very simple to the complex ones. This metalloenzyme superfamily includes six distinct genetic families (the α-, β-, γ-, δ-, ζ-, and η-CAs) known to date, which constitute an interesting example of convergent evolution at the molecular levelCitation38–42. These six CA families vary in their preference for the catalytic metal ions used within the active siteCitation43–45, since Zn2+, Cd2+, or Fe2+ can be used within their active sitesCitation46–52. The α-CA isoforms differ significantly in their localization and tissue distribution. CA I, II, III, VII, and XIII are cytosolic isoforms, CA IV, IX, XII, and XIV are membrane-bound, CA VA and VB are mitochondrial, whereas CA VI is secreted. CA IX and XII are known as the membrane tumor-associated CAs, being found in a limited number of normal tissues, such as the gastrointestinal mucosa and body cavity liningCitation53–55. An important role of CA IX and XII as tumor pH-regulating enzymes, involved in the survival/proliferation of the tumor cells within the hypoxic, acidic niche typical of many solid cancersCitation56–59.

Cholinesterases (ChE) are an enzyme family that catalyze the hydrolysis of acetyl choline (ACh) into choline and acetic acid, an essential process for the restoration of the cholinergic neurotransmission. There are two cholinesterase types: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8)Citation11,60–64. AChE is known to be abundant in the muscle, brain, and erythrocyte membrane, whereas BChE has a higher activity in liver, intestine, heart, kidney, and lungCitation65. AChE and BChE share 65% amino acid sequence homology and have similar molecular forms and active sites despite being products of different genes on the human chromosomesCitation66. Both cholinesterases participate in cholinergic neurotransmission by hydrolyzing ACh in the central and peripheral nervous systemCitation67. The symptomatic Alzheimer’s disease (AD) treatment involves the use of cholinesterase inhibitors (ChEIs) such as Rivastigimine. ChEIs are the first-line drugs in the symptomatic treatment of AD, as by inhibiting cholinesterase they lead to an increased synaptic level of the neurotransmitterCitation68,Citation69.

Lactoperoxidase (LPO, E.C.1.11.1.7) is of growing interest due to its distinctive biological activity, such as biocidal and biostatic onesCitation70–73. The mechanism of the LPO antimicrobial action has been studied thoroughly regarding the conversion of thiocyanate (SCN−) to antimicrobial products, such as hypothiocyanite ion (OSCN−), hypothiocyanous acid (HOSCN), and some other highly reactive and short-lived oxidation products. These oxidations occur in the presence of hydrogen peroxideCitation74–77. LPO, a member of the mammalian peroxidase family, with antibacterial properties is found in the salivary glands, in the breast secretory epithelial cells, lacrimal glands and in their secretions, such as saliva, milk, and tearsCitation78–80. Based on its antibacterial characteristics, currently LPO has extensive applications including preservation of raw milk during collection or transportation to processing plants in dairy industry, the extending shelf-life of pasteurized milk, and the supplementation of salivary peroxidase antimicrobial system in toothpastes and mouth rinses to reduce acid production by oral microorganismsCitation81.

Glutathione S-transferases (GST, EC 2.5.1.18) belong to the superfamily of phase II detoxification enzymes. They are multifunctional enzymes for the cellular defense against xenobiotics and provide protection for organism. They are essential and found in all kingdoms of lifeCitation82. The subfamily of GSTs is further distinguished into at least 14 classes (α-, β-, δ-, ɛ-, ζ-, θ-, κ-, λ-, μ-, π-, s-, τ-, ϕ-, and Ω-GST)Citation83. This classification is based on the substrate specificity, sensitivity to inhibitors, N-terminal amino acid sequence and antibody cross-reactivity. Each GST contains a G-site, which is the glutathione substrate binding site and an H-site, which is hydrophobic substrate binding siteCitation82. The G-site is conserved in the N-terminal region among the different enzyme classes. On the other hand, the H-site is highly diverse, being characterized by a significant variation in sequence and topology and thus accounting for the variability of enzyme activity in the GST superfamilyCitation83.

In this study, we investigated the inhibition effect of CAPE against human carbonic anhydrase (hCA) isoenzymes hCA I, II, IX, and XII, AChE, BChE, LPO, and GST.

Experimental section

Determination of hCA isoenzymes activity and inhibition

An Applied Photophysics stopped-flow instrument was used to assay the catalytic/inhibition of four CA isozymes, as reported by KhalifahCitation84. Briefly, phenol red (20 mM) was used as an indicator, with an absorbance maximum of 557 nm, with HEPES (10 mM, pH 7.4) as a buffer and 0.1 M Na2SO4 or NaClO4 for maintaining constant the ionic strength; these anions are not inhibitory at the used concentration. The CA-catalyzed CO2 hydration was followed for a period of 10–100 s.

For the determination of the kinetic parameters and inhibition constants, the saturated CO2 concentrations ranged from 1.7 mM to 17 mM. For CAPE, at least six traces of the initial 5–10% of the reaction were used for determining the initial velocity. The uncatalysed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitor (10 mM) were prepared in distilled–deionized water, and dilutions up to 0.01 μM were performed with distilled–deionized water. CAPE and enzyme solutions were preincubated together for 15 min at room temperature prior to the assay to allow for the formation of the EI complex. The inhibition constant of CAPE was obtained by non-linear least-squares methods using PRISM 3, as reported earlier, and represents the mean from at least three different determinations. All hCA isozymes were prepared in recombinant form as reported earlier by our groupCitation85–87.

Determination of AChE/BChE activity

The inhibitory effect of CAPE on AChE/BChE activities were measured according to spectrophotometric method of Ellman et al.Citation88 Acetylthiocholine iodide or butyrylthiocholine iodide (AChI/BChI) were used as substrates of the reaction. 5,5′-Dithio-bis(2-nitro-benzoic)acid (DTNB, D8130-1G, Sigma-Aldrich, Steinheim, Germany) was used for the measurement of the AChE/BChE activities. Briefly, 100 mL of Tris/HCl buffer (1 M, pH 8.0), 10 mL of sample solution dissolved in deionized water at different concentrations and 50 mL AChE/BChE (5.32 × 10−3 U) solution were mixed and incubated for 10 min at 25 °C. Then 50 mL of DTNB (0.5 mM) was added. The reaction was then initiated by the addition of 50 mL of AChI/BChI. The hydrolysis of these substrates was monitored spectrophotometrically by formation of the yellow 5-thio-2-nitrobenzoate anion as the result of the reaction of DTNB with thiocholine, released by enzymatic hydrolysis of AChI/BChI, with an absorption maximum at a wavelength of 412 nmCitation81,Citation89.

Purification studies of lactoperoxidase

Cyanogen bromide-activated-Sepharose 4B was used for purification of LPO from bovine milk according to the method of Atasaver et al.Citation79 The purity of LPO was checked by sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS-PAGE)Citation90 as previously reportedCitation91–93. Protein concentration was determined according to the Bradford methodCitation94. The stacking and running gels contained 3% (w/v) and 10% (w/v) acrylamide, respectively, and 0.1% (w/v) SDS, according to a previously published procedureCitation95–99.

Determination of acetylcholinesterase and butyrylcholinesterase inhibition

In order to determine the effect of CAPE on AChE, different CAPE concentrations were added into the reaction medium. The enzyme activity was measured, and an experiment in the absence of drug was used as controlCitation66. The IC50 values were obtained from activity (%) versus CAPE concentration plots. To determine the Ki constant in the media with CAPE as inhibitor, different substrate (ACh/BCh) concentrations were used. Inhibitor solution was added into the reaction medium, resulting in three different fixed concentrations of inhibitor. Lineweaver–Burk graphsCitation100 were used to determine Vmax and other kinetic parameters. The Ki was calculated from these graphs.

Determination of glutathione S-transferase inhibitions

The kinetic constants of GST-catalyzed reaction were determined using 2,4-dinitrochlorobenzene (25 mM, 20 μL, %95'lik), or glutathione (20 mM, 50 μL) in sodium phosphate buffer (pH 7.2, 50 mM, 200 μL) at room temperature. GST activity was measured as described previouslyCitation101. The enzyme solution replaced by phosphate buffer was used as the control. The rate of reaction was used to construct a double-reciprocal Lineweaver–Burk plot of 1/V versus 1/S and the kinetic constantsCitation100. Also, in this experiment, varying CAPE concentrations were used to measure their ability to inhibit the GST. CAPE solution was added into the reaction medium, resulting in three different fixed concentrations of CAPE as inhibitor.

Results and discussion

Phenols are biologically active substances and possess antioxidant, anticancer, antimutagenic, anticarcinogenic, antiviral, antibacterial, and anti-inflammatory activitiesCitation102–104. CAPE is an active phenolic component of honeybee propolis and has been used as a folk medicine for many yearsCitation14. CAPE has a possible beneficial effect on antioxidant enzyme activity in diabetic rats. It inhibits lipid peroxidation and regulates antioxidant enzymes in the diabetic heartCitation105. CAPE was able to inhibit the gene expression; production and the activity of matrix metalloproteinases induced by lipopolysaccharide and also increased the gene expression of human monocytic cell lineCitation106. At the molecular level, it modulates the activities of focal adhesion kinaseCitation107, inducible human immunodeficiency virus integraseCitation108, nitric oxide synthaseCitation109, lipoxygenaseCitation110, and cyclooxygenase (COX)Citation111. CAPE also inhibits proliferation of human keratinocytes and interferes with the epidermal growth factor regulation of ornithine decarboxylaseCitation112. It was reported that it blocks neuronal death through inhibiting inflammation and mitochondrial cytochrome c releaseCitation113. Since nitric oxide synthesized by inducible nitric oxide synthase has been known to be involved in inflammatory and autoimmune-mediated tissue destruction. Also, CAPE inhibits nitric oxide synthase gene expression and enzyme activityCitation109. With regard to the anti-inflammatory action of CAPE, it has been reported that CAPE inhibits the enzyme activities of COX. In addition, it suppresses the transcriptional expression of COX, resulting in diminished synthesis of prostaglandins, the major mediators of inflammationCitation111,Citation114. It was reported that pretreatment with intraperitoneal CAPE significantly diminished the tissue myeloperoxidase activityCitation115. CAPE blocks production of reactive oxygen species in human neutrophils and xanthine/xanthine oxidase systemCitation110. In the present study, CAPE significantly reduced the high nitric oxide levels and adenosine deaminase activityCitation116. It was reported that the neuroprotective effect of CAPE could be related to the inhibition of caspaseCitation117.

Phenolic compounds are slightly acidic and have weak tendencies to lose the proton (H+) ion from the hydroxyl group (–OH), resulting in the highly water-soluble phenolate anion. Phenols effectively inhibit CA isoenzymesCitation45. The inhibition profile of various isozymes with this class of agents is variable, with inhibition constants ranging from the millimolar to the submicromolar range for many simple phenolsCitation45. Also, they inhibit the CA isozymes because of the presence of different functional groups in their scaffold, mainly the phenolic -OH and -COOH groups, which may bind to the Zn(II) ion or the water coordinated to the zinc ion from the CA active siteCitation39. In addition to the well-known sulfonamides, sulfamates, and sulfamides, phenolic compounds are another type of effective carbonic anhydrase inhibitorsCitation39,Citation118. The classical CAIs are the primary sulfonamides, which are in clinical use as diuretics and systemically acting antiglaucoma drugsCitation119. The design of CAIs as therapeutic agents is related to the large number of isoforms in humans, their rather diffuse localization in many tissues or organs. CAIs have lately emerged that CAIs could have potential as anticancer, anti-obesity, and anti-infective drugsCitation31,41,55,120–123.

Phenolic compounds may constitute interesting lead molecules for identifying novel CAIs. Here, we report the inhibition effect of CAPE on four catalytically active isoforms, hCA I, II, IX, and XII, as well as against AChE, BChE, LPO, and GST. CAPE possesses two phenolic moieties in its scaffolds. We discovered nanomolar inhibition against some of these metabolic enzymes. The inhibition data of CAPE reported here are shown in , and the following comments can be drawn from these data:

  1. Cytosolic hCA I is expressed in the body and can be found in high concentrations in the blood and gastrointestinal tract. CAPE exhibited a weak inhibitory activity against this cytosolic isoenzyme hCA I with a Ki values 3.467 μM (). On the other hand, in another study, we found that acetazolamide (AZA), which is used as clinical CAs inhibitor and treatment of glaucoma, cystinuria, altitude sickness, epilepsy, periodic paralysis, idiopathic intracranial hypertension, dural ectasia, and central sleep apnea had been shown Ki value 0.184 μMCitation45. In our previous study, we determined the effect of CAPE on hCA I (Ki: 115.0 μM), and II (Ki: 473.0 μM) purified from human erythrocyte using Sepharose-4B-L-tyrosine-sulphanilamide affinity chromatographyCitation14. It has been reported that phenolics are not biologically active unless substitution at either the ortho- or para-position has increased the electron density at the –OH group and lowered the oxygen–hydrogen bond energy. As can see in , CAPE has two –OH groups at para-position.

  2. With regard to the profiling assay against cytosolic hCA II, CAPE was slightly more active, with a Ki value 0.797 μM. For comparison, AZA, which was used as clinical CAs inhibitor showed a Ki value 0.061 μMCitation43. This result clearly showed that CAPE is a rather effective inhibitor for the cytosolic isoform hCA II. Many studies have demonstrated that the inhibition of CA II is due to the ability of an inhibitor to mimic the tetrahedral transition state when binding to the catalytic Zn2+ located in the active site. CA II protein fold, Zn2+ ion, and its coordination by histidine residuesCitation124. It was reported that phenols, which bind by interacting with a water molecule/hydroxide ion coordinated to Zn2+ through hydrogen bondingCitation85. The physiologically dominant cytosolic isoform hCA II is ubiquitous and is being involved in several diseases, such as epilepsy, edema, glaucoma, and altitude sicknessCitation125.

  3. So far, 16 isoforms of hCA have been discovered; among them the dimeric transmembrane glycoproteins hCA IX and XII are also human associated CA isoforms having extracellular active site and are found in a broad spectrum of hypoxic tumor typesCitation125,Citation126. Many sulfonamide derivatives have been investigated for their CA inhibition activity in the search for selective hCA IX and hCA XII inhibitors because their lack of selectivity is the major challenge for the wide use of chemotherapeutic agents in cancer therapyCitation43. Both CA IX and XII are overexpressed in many such tumors in response to the hypoxia inducible factor pathway, and research on the involvement of these isozymes in cancer has progressed significantly in recent yearsCitation125,Citation127. hCA IX showed moderate inhibition activity with CAPE, with an inhibition constant of 4.258 μM.

  4. hCA XII was also poorly inhibited by CAPE, with a Ki value of 4.467 μM. On the other hand, AZA, a positive standard for CA inhibition, showed an effective inhibitory activity with a Ki value 0.006 μMCitation43.

  5. The compounds possessing AChE inhibitory effects are used for the treatment of AD. However, these drugs have many undesired side effects. Thus, the development and utilization of new effective antioxidants as well as AChE compounds is highly desiredCitation47. Currently the most prescribed ChEIs are donepezil, galantamine, and rivastigmine. These drugs are used to treat patients with mild-to-moderate ADCitation128. BChE has a specific role in cholinergic neurotransmission and it has been associated with ADCitation129. Individual ChEIs differ from each other with respect to their pharmacologic properties. Donepezil and galantamine are short-acting reversible competitive inhibitors, whereas rivastigmine is actively metabolized by ChE. Primary target of donepezil and galantamine is AChE, however, rivastigmine shows equal affinity for both AChE and BChE enzymesCitation130. These agents do not stop disease progression, but clinical studies have shown that they temporarily stabilize cognitive impairment and help to maintain global function, often delaying the need for patient placement in nursing homes by several monthsCitation131. BChE levels in the body exceed those of AChE in all tissues except muscle and brain. The human body contains ten times more BChE than AChECitation132. It was reported that in AD, AChE is lost up to 85% in specific brain regions, whereas BChE levels rise with disease progressionCitation129,Citation133. It was also shown that the main AChE inhibitory effect was primarily associated with aromatic compounds and, to a lesser degree, with aliphatic compoundsCitation134. AChE was very effectively inhibited by CAPE, with Ki value of 51 793 nM (). The Ki value of CAPE for AChE was calculated from Lineweaver–Burk plotsCitation100. On the other hand, donepezil hydrochloride, which is used for the treatment of mild-to-moderate AD and various other memory impairments, had been shown to lower AChE inhibition activity (IC50 of 55 nM)Citation135.

  6. It was reported that caffeine has therapeutic role on cholinergic systemCitation136. LPO is very important protein owing to the fact that LPO is found in the milk of all mammals. Our investigation showed CAPE inhibited LPO with a Ki value of 430.03 nM.

  7. Recently, many studies demonstrated that GST plays important functions in cellular defense against chemical toxicity. It was reported a link between the lack of GST enzyme activity and the susceptibility to develop different types of cancer including oral, gastric, and bladder cancersCitation137. GST was effectively inhibited by CAPE, with a Ki value of 0.453 nM (). It was reported that the inhibitor of GST-bearing suitable linkers could concomitantly bind to two active sites of GST and usually possess Ki values at nanomolar levels and excellent enzyme-selectivityCitation138.

Figure 1. Chemical structures of caffeic acid phenethyl ester (CAPE).

Figure 1. Chemical structures of caffeic acid phenethyl ester (CAPE).

Table 1. Inhibition constants (Ki) of caffeic acid phenethyl ester (CAPE) against four human carbonic anhydrase isoenzymes (hCA I, II, IX, and XII) acetylcholinesterase enzyme (AChE), butyrylcholinesterase enzyme (BChE), lactoperoxidase enzyme (LPO), and glutathione S-transferase (GST) enzyme.

Conclusion

The effect of CAPE against hCA I, II, IX, XII isoenzymes, AChE, BChE, LPO, and GST was evaluated. CAPE demonstrated micromolar inhibition against four CA isoenzymes, nanomolar inhibition against LPO, and GST, picomolar inhibition against AChE, and BChE. The results showed that CAPE moderately inhibited four CA isoenzymes but effectively inhibited the other metabolic enzymes (AChE, BChE, LPO, and GST) with diverse inhibition profiles. These data may explain the beneficial health effects of some of these compounds and may lead to enzyme researchers and drug design campaigns.

Acknowledgements

This work was financed in part by two EU projects of the 7th FP, Metoxia and Dynano. Also, IG and SE would like to extend his sincere appreciation to the Research Chairs Program at King Saud University for providing funding to this research.

Declaration of interest

The authors have declared no conflict of interest.

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