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Thymol, chemically known as 2-isopropyl-5-methylphenol is a colorless crystalline monoterpene phenol. It is one of the most important dietary constituents in thyme species. For centuries, it has been used in traditional medicine and has been shown to possess various pharmacological properties including antioxidant, free radical scavenging, anti-inflammatory, analgesic, antispasmodic, antibacterial, antifungal, antiseptic and antitumor activities. The present article presents a detailed review of the scientific literature which reveals the pharmacological properties of thymol and its multiple therapeutic actions against various cardiovascular, neurological, rheumatological, gastrointestinal, metabolic and malignant diseases at both biochemical and molecular levels. The noteworthy effects of thymol are largely attributed to its anti-inflammatory (via inhibiting recruitment of cytokines and chemokines), antioxidant (via scavenging of free radicals, enhancing the endogenous enzymatic and non-enzymatic antioxidants and chelation of metal ions), antihyperlipidemic (via increasing the levels of high density lipoprotein cholesterol and decreasing the levels of low density lipoprotein cholesterol and low density lipoprotein cholesterol in the circulation and membrane stabilization) (via maintaining ionic homeostasis) effects. This review presents an overview of the current in vitro and in vivo data supporting thymol’s therapeutic activity and the challenges concerning its use for prevention and its therapeutic value as a dietary supplement or as a pharmacological agent or as an adjuvant along with current therapeutic agents for the treatment of various diseases. It is one of the potential candidates of natural origin that has shown promising therapeutic potential, pharmacological properties and molecular mechanisms as well as pharmacokinetic properties for the pharmaceutical development of thymol.
Keywords:
thymol, antioxidant, free radical scavenger, cancer, animals, drug discovery, phytochemicals, natural compounds
The protective effects of thymol in renal diseases are represented in Table and the schema of the protective effects of thymol shown in the studies are represented in Figure . Thymol (20 mg/kg) was shown to inhibit cisplatin-induced renal injury by attenuating oxidative stress, inflammation and apoptosis in male adult Swiss Albino rats (El-Sayed et al., 2014). Thymol (200–500 μM) induced Ca2+ release from the ER which facilitated the entry of Ca2+ via store-operated Ca2+ entry in Madin-Darby canine kidney (MDCK) renal tubular cells. Thymol triggers cell death by promoting apoptosis mediated by ROS in MDCK renal tubular cells (Chang et al., 2014). Thymol’s (50 and 150 mg/kg) beneficial effect on cisplatin-induced renal injury in mice was also demonstrated by quantitative renal dimer captosuccinic acid (99mTc-DMSA) uptake concomitant to potent antioxidant and anti-inflammatory properties. 99mTc-DMSA uptake per gram tissue of kidneys in %ID/g was 65.02 ± 32.21 and 88.46 ± 20.46 in the thymol (50 and 150 mg/kg) treated mice induced with cisplatin. Furthermore, Thymol administration increased the level of %ID/g (Hosseinimehr et al., 2015).
The protective effects of thymol in liver diseases are represented in Table .
Thymol (30 mg/100 g) has been shown to inhibit oxidative stress in hydrocortisone-induced hepatotoxicity in rats by attenuating lipid peroxidation and enhancing antioxidant defense in the liver. Thymol treatment reinstated the activities of liver marker enzymes attributed to its potent free radical scavenging and antioxidant activity (Aboelwafa and Yousef, 2015). Thymol (300 mg/kg) has been shown to attenuate carbon tetrachloride induced liver injury in mice. Thymol treatment reduced lipid peroxidation and increased the status of antioxidants thereby preventing oxidative stress mediated hepatic injury in mice. Liver function tests and histological studies confirmed the other biochemical findings of the study (Al-Malki, 2010). In carbon tetrachloride (CCl4) (20 μl/kg) induced liver injury, thymol (300 mg/kg) abrogated lipid peroxidation and reinstated the normal activities of hepatic marker enzymes in the liver due to its potent free radical scavenging property (Alam et al., 1999).
Thymol (150 mg/kg) showed to inhibit paracetamol induced hepatotoxicity in mice by preventing the alterations in the activities of hepatic marker enzymes (Janbaz et al., 2003). Thymol (50 μg/ml) inhibited oxidative damage to liver cells by inhibiting ROS overproduction, ameliorating lipid peroxidation, preventing apoptosis and increasing antioxidant levels in tert-butyl hydroperoxide (t-BHP) induced Chang liver cells (Kim et al., 2014). Thymol (125 mg/kg) attenuated CCl4 induced hepatoxicity by inhibiting the release of glutamic pyruvate transaminase into the serum and it also decreased the levels of MDA in female Swiss OFFI mice (Jimenez et al., 1993). Thymol (1 ml/kg and 5.6 ml/kg) from thyme tincture and syrup inhibited CCl4 induced liver injury by reducing lipid peroxidation mediated oxidative stress and it maintained the levels of hepatic markers in Wistar rats (Raskovic et al., 2015). Thymol (50–200 mg/kg) increased the activities of phase I enzymes such as 7-ethoxycoumarin O-deethylase (ECOD) and phase II enzymes such as GST and quinone reductase (QR) along with raised activities of GST alpha and GST micro in mouse liver (Sasaki et al., 2005). In t-BHP induced Chang liver cells, thymol (50 μg/ml) inhibited lipid peroxidation and apoptosis by increasing the status of the antioxidants (Kim et al., 2014). These results revealed that thymol imparts a hepatoprotective effect on t-BHP-induced oxidative injury by mediating antioxidant activity (Kim et al., 2014). Thymol (25–100 μM) increased both enzymatic and non-enzymatic antioxidants and inhibited lipid peroxidation against paracetamol-induced toxicity in human HepG2 cells (Palabiyik et al., 2016).
The protective effects of thymol in reproductive disorders are represented in Table .
Male infertility refers to the inability of males to cause pregnancy in females usually due to reduced sperm quantity and quality (Cooper et al., 2009). Thymol (400 mg/kg) decreased fertility in male albino Wistar rats. Thymol decreased the weight of testis, sperm count and motility and increased the amount of abnormal sperms in rat testis (Surendra Kumar et al., 2011). Chikhoune et al. (2015) revealed the anti-fertility effect of thymol in human spermatozoa. Thymol (100–500 μg/ml) dose dependently decreased sperm count, sperm motility, sperm vitality in human sperm. These two studies have revealed that thymol could be used as a standard contraceptive agent in humans.
The protective effects of thymol in metal induced toxicity are represented in Table .
Chromium is a naturally occurring, highly toxic transition metal due to its strong ability to oxidize cellular components through its passive entry via cellular membranes into cells (O’Brien et al., 2003). Thymol (2.5 μg/ml) has been shown to inhibit hexavalent chromium induced oxidative damage in rat erythrocytes. Thymol treatment significantly decreased MDA levels, hemolysis, erythrocyte destabilization and increased the activities of antioxidants enzymes and improved the levels of glutathione in rat erythrocytes (Abd-Elhakim and Mohamed, 2016).
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Arsenic and mercury are toxic metals found in nature in soil, in industrial and agrochemicals as well as pharmaceuticals. Upon exposure, they are known to cause acute and chronic disease and mainly affect smooth muscles of the cardiovascular and respiratory systems. Thymol (0–200 μM/L) abrogated arsenic and mercury induced hyper contraction of both aortic and tracheal smooth muscles by inhibiting Ca2+ influx at low concentrations. It also neutralizes ROS and inhibits Ca2+ influx at higher concentrations (Kundu et al., 2016). Thymol (100 μM) was shown to protect against cytotoxicity and genotoxicity induced by mercuric chloride in the human HepG2 cell line due to its potent free radical scavenging ability that in reflected in the attenuation of mitochondrial and oxidative damage (Shettigar et al., 2015). Thymol present in the essential oil of T. lanceolatus (IC50= 256.17 μg/ml) was shown to induce cytotoxicity and cell proliferation in HepG2 cells (Khadir et al., 2016).
The structural alterations into the phenol structures, like introducing a polar hydroxymethyl moiety, could enhance its antioxidant activity compared to parent compounds (Torres de Pinedo et al., 2007). The derivative of thymol, named 4-(hydroxymethyl)-2-isopropyl-5-methylphenol, was synthesized by the hydroxymethylation of thymol (Mastelic et al., 2008). The phenolates as nucleophiles reacted with methanol which yielded hydroxymethylphenols at alkaline pH. This might be due to the delocalization of the phenolate ion charge between the phenolate oxygen and its respective ortho and para- carbons. The steric effect of the isopropyl group was believed to confer improved antioxidant activity and reduced mitochondrial activity of thymol derivative in HeLa cells in a concentration dependent manner (Mastelic et al., 2008).
A set of new thymol derivatives invented and patented recently showed potent antitumor activity against A549, SKOV-3, human melanoma cells (SK-MEL-2), cellosaurus cells (XF498) and colorectal adenocarcinoma cells (HCT15 cells) (Zee et al., 2001). Thymol analogues such as 4-morpholinomethyl-2-isopropyl-5-methylphenol (THMO) and 4-Pyrrolidinomethyl-2-isopropyl-5-methylphenol (THPY) were synthesized by the reaction between thymol and formaldehyde with morpholine or pyrrolidine (Shen et al., 2005). These two analogs of thymol showed a potent superoxide anion scavenging effect in vitro and in human blood neutrophils and also possess a superior lipid peroxidation inhibitory effect via the attenuation of enzymes involved in antioxidant defense. In the two thymol analogs, THMO revealed potent antioxidant activity with IC50 values of 21.72 and 61.29 μM for the inhibition of xanthine oxidase and lipid peroxidation (Shen et al., 2005). THMO (10 mM) also decreased the peak amplitude of L-type inward current of Ca2+ (ICa,L) in NG108-15 cells as analyzed by the patch-clamp technique. These reports have revealed that the antioxidative action of the thymol analogs is linked with its capacity of inhibiting Ca2+ current (Shen et al., 2005). This study suggests that THMO could be a suitable candidate for the treatment of free radical related disorders by virtue of its antioxidant and Ca2+ ion current inhibition activity.
Microencapsulation is a tool frequently used in pharmaceutical, food, cosmetic, and agrochemical industries. The encapsulation of thymol in microspheres made up of natural polymers such as methylcellulose and hydroxylpropyl methylcellulose phthalate can serve to obtain efficient delivery of this phytochemical as adjuvants or current medications for the treatment of infectious diseases and compensate the limited bioavailability due to its lower solubility (Rassu et al., 2014). The core-shell or matrix particle encapsulation of essential oils has been investigated to determine their controlled release (Martins et al., 2014). The encapsulation of thymol into methylcellulose microspheres by spray drying remarkably increases the bioavailability compared to free thymol and it can be suggested to be used for the treatment of intestinal infections (Rassu et al., 2014).
The synthetic, natural and semisynthetic polymers play a crucial role in drug release formulations and nowadays these are used as efficient drug carriers (Nayak et al., 2009). Cellulose derivatives have been used for sustained release matrices, delayed release dosage forms, binders in granules and tablets and they also have many other applications (Chambin et al., 2004). Zamani et al. (2015) has structured the matrix polymer encapsulation of thymol by the emulsion solvent evaporation method with hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose (EC) to increase the duration of action of thymol. Both polymers have shown a considerable effect on drug release behavior, efficiency of drug entrapment, drug loading and particle size, whereas the formulation F6 revealed a controlled effect compared to the other formulations in in vitro release (Zamani et al., 2015).
A co-drug DTH has been developed recently by Dhaneshwar et al. (2013). Diacerein, an IL-1β inhibitor possesses anti-arthritic and moderate anti-inflammatory properties (Dhaneshwar et al., 2013). This mutual prodrug was developed by the covalent linkage of thymol with the carboxylic acid (-COOH) group of diacerein and this prodrug showed lessened irritant effect, improved absorption, prolonged drug release with improved anti-inflammatory effect. The hydrophobic nature of thymol enhanced the lipophilicity of diacerein which could be responsible for its enhanced bioavailability and its better absorption. The synthesis of DTH was done by the dicyclohexylcarbodiimide (DCC) coupling method (Holmberg and Hansen, 1979) and its physicochemical characterization was evaluated using spectral analysis. DTH was very stable in acidic pH conditions of the stomach and complete diacerein release was observed in phosphate buffer (91–94%) (pH 7.4) and in the small intestine.
Thymol has been used as an antioxidant agent in this design and its selection was justified after the promising anti-inflammatory and anti-arthritic effect of DTH against osteoarthritis compared to standard drugs which is attributed to the pharmacological effects of thymol. DTH attenuated FCA induced chronic synovitis in rats by its marked antiarthritic effect compared to the moderate effect of diacerein and mild effect of thymol. The authors suggested that the combination of diacerein with thymol could be promising therapeutic approach in inflammation related diseases (Dhaneshwar et al., 2013).
The need for alternative therapies with less toxic effects for various human ailments is evident. The findings from various studies reviewed herein showed the role of thymol in the prevention of various types of diseases through its multi-pharmacological properties from antioxidant to anti-tumor ones. Thymol containing plants have been used in traditional medicine for management of various diseases such as many cancer types, cardiovascular diseases, diabetes, and neurodegenerative diseases. Multiple pharmacological and molecular mechanisms of action for its preventive and therapeutic effects have been demonstrated based on its molecular targets identified in numerous studies. While a great number of in vitro studies for numerous diseases including cancer and cardiovascular diseases have been reported, more in vivo studies should be undertaken to confirm the in vitro findings. In addition, there is a contradiction between in vitro concentrations and in vivo doses in certain types of cancer. Thus, pharmacokinetics and pharmaceutical studies are needed to interpret the inconsistency between in vitro and in vivo results. These reported features along with the minimal side effects, cost effectiveness and easy access made thyme and its constituent thymol an effective therapeutic agent for the management of numerous chronic diseases. Furthermore, thymol, being abundantly and ubiquitously present in numerous plants, could be available for dietary use. Its administration and benefits could be achieved in a simpler way through normal daily diet. However, the vast majority of the data is preclinical, and further clinical studies are warranted. Furthermore, comprehensive toxicological studies should be conducted to support the safety of thymol in animal models to progress for clinical studies. Though, taking together all the studies, it is significant to say that research on thymol as a drug candidate is progressive and encouraging. This has been well demonstrated by the publication patterns year after year. Hence, thymol is one of the most powerful contenders in the race of phytochemicals of natural origin with polypharmacological properties displaying potent preventive and therapeutic properties against various human diseases.
SO and MN conceptualized and outlined the study. MN drafted the manuscript. HAT, SA, HJ, and SO edited and reviewed the manuscript. SO and MN throughly re-reviewed it and all authors approved it.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer FPG and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.
The research in laboratory of Shreesh Ojha is supported by the University Program for Advanced Research (UPAR) and Center-Based Interdisciplinary grants from the Office of the Deputy Vice Chancellor of Research and Graduate Studies of United Arab Emirates University, Al Ain, UAE.
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