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Effects of thymol (0.02-2 mM) on the electrical and mechanical activities of the smooth muscle cells of the guinea-pig taenia coli were investigated with either micro-electrode or double sucrose gap methods.1. Thymol, in a concentration of more than 0.03 mM, reduced the amplitude and maximum rate of rise of the spikes without any change of the membrane potential. When the concentration was increased to 0.3 mM, thymol completely blocked the spontaneous and evoked spike activities. In a concentration of more than 0.1 mM, thymol reduced the membrane resistance in proportion to the concentration without any change of the membrane potential.2. Ionic mechanisms involved in the effects of thymol on the membrane resistance were investigated in various ionic environments. The results showed that in concentrations below 0.5 mM thymol might selectively increase the Cl-conductance of the membrane. Participations of Na and K ion in the effects of thymol on the membrane resistance could be eliminated. However, at more than 1 mM, thymol increased the membrane conductance non-selectively. Excess Ca in the external solution partly suppressed the action of thymol on the taenia coli.3. Potentiation of the twitch tension was not observed on treatment with any concentration of thymol.4. After pre-treatment with thymol (0.5 mM), isotonic K Krebs solution depolarized the membrane and reduced the membrane resistance as observed in the absence of thymol. However, thymol completely suppressed the K-induced contracture.5. Application of excess Ca and acetylcholine during the maintained contracture evoked by isotonic K Krebs solution induced further development of the contracture. However, on pre-treatment with thymol, neither excess Ca nor acetylcholine could evoke a mechanical response in isotonic K Krebs solution.6. The results obtained from the present experiments are discussed in relation to the roles of Ca on the smooth muscle cells.
Thymol (5-methyl-2-isopropylphenol) is a phenolic compound that is used to inhibit oral bacteria. Because little is known regarding the effects of this compound on ruminal microorganisms, the objective of this study was to determine the effects of thymol on growth and lactate production by the ruminal bacteria Streptococcus bovis JB1 and Selenomonas ruminantium HD4. In addition, the effect of thymol on the in vitro fermentation of glucose by mixed ruminal microorganisms was investigated. Neither 45 nor 90 microg/ml of thymol had any significant effect on growth or lactate production by S. bovis JB1, but 180 microg/ml of thymol completely inhibited growth and lactate production. In the case of S. ruminantium HD4, 45 microg/ml of thymol had little effect on growth and lactate production; however, 90 microg/ml of thymol completely inhibited growth of S. ruminantium HD4. Thymol also decreased glucose uptake by whole cells of both bacteria. When mixed ruminal microorganisms were incubated in medium that contained glucose, 400 microg/ml of thymol increased final pH and the acetate to propionate ratio and decreased concentrations of methane, acetate, propionate, and lactate. In conclusion, thymol was a potent inhibitor of glucose fermentation by S. bovis JB1 and S. ruminantium HD4. Even though thymol treatment decreased methane and lactate concentrations and increased final pH in mixed ruminal microorganism fermentations of glucose, concentrations of acetate and propionate were also reduced.
A reliable and sensitive method was developed for determination of thymol in human plasma by automated headspace solid-phase microextraction (SPME). After enzymatic cleavage of thymol sulfate thymol was extracted by a 65 microm polydimethylsiloxane-divinylbenzene crimped fiber (Supelco) after addition of sodium chloride and phosphoric acid (85%). Desorption of the fiber was performed in the injection port of a gas chromatograph at 220 degrees C (HP 5890; 50 m x 0.2 mm I.D., 0.2 microm HP Innowax capillary column; flame ionization detection). Fibers were used repeatedly up to 40 analysis. The recovery was 5% after 35 min of extraction. The calibration curve was linear in the range of 8.1-203.5 ng ml(-1) with a limit of quantitation (LOQ) of 8.1 ng ml(-1). The within-day and between-day precision and accuracy were < or = 20% at the LOQ and <15% at higher concentrations according to international guidelines for validation of bioanalytical methods. After administration of a thymol-containing herbal extract only thymol sulfate, no free thymol, could be detected in human plasma, thus analysis of thymol was after enzymatic cleavage of thymol sulfate. It is concluded that the newly developed automated method can be used in clinical trials on bioavailability and pharmacokinetics of thymol-containing herbal medicinal products.
Essential oil compounds such as found in thyme extract are established for the therapy of chronic and acute bronchitis. Various pharmacodynamic activities for thyme extract and the essential thyme oil, respectively, have been demonstrated in vitro, but availability of these compounds in the respective target organs has not been proven. Thus, investigation of absorption, distribution, metabolism, and excretion are necessary to provide the link between in vitro effects and in vivo studies. To determine the systemic availability and the pharmacokinetics of thymol after oral application to humans, a clinical trial was carried out in 12 healthy volunteers. Each subject received a single dose of a Bronchipret TP tablet, which is equivalent to 1.08 mg thymol. No thymol could be detected in plasma or urine. However, the metabolites thymol sulfate and thymol glucuronide were found in urine and identified by LC-MS/MS. Plasma and urine samples were analyzed after enzymatic hydrolysis of the metabolites by headspace solid-phase microextraction prior to GC analysis and flame ionization detection. Thymol sulfate, but not thymol glucuronide, was detectable in plasma. Peak plasma concentrations were 93.1+/-24.5 ng ml(-1) and were reached after 2.0+/-0.8 hours. The mean terminal elimination half-life was 10.2 hours. Thymol sulfate was detectable up to 41 hours after administration. Urinary excretion could be followed over 24 hours. The amount of both thymol sulfate and glucuronide excreted in 24-hour urine was 16.2%+/-4.5% of the dose.
Thymol stimulated O2- production in guinea pig neutrophils. O2- production occurred about 30 sec after the addition of thymol, and its rate was independent of extracellular Ca2+. Thymol-induced activity was inhibited by trifluoperazine (TFP), an inhibitor of protein kinase c, and its IC50 was less than that for 12-O-tetradecanoyl phorbol 13-acetate (TPA) induced activity. After complete activation, O2- production was reversed by addition of TFP or by washing out and resuspending in a stimuli-free medium. The responsiveness of the thymol-pulsed cells to another stimulus, TPA, was somewhat more than resting cells, but the responsiveness of the former cells to thymol was about half that of the latter cells. The ATP level of cells was reduced to one half its initial value during activation by thymol. These data suggest that the magnitude of thymol-induced O2- production in neutrophils is dependent on the initial density of the binding sites of the cells with thymol and the initial intracellular ATP concentration.
BACKGROUND AND OBJECTIVE: Thymol is a naturally occurring phenol derivative used in anaesthetic practice as a stabilizer and preservative of halothane, usually at a concentration of 0.01%. Although analgesic effects have long been described for thymol and its structural homologue menthol, a molecular basis for these effects is still lacking. We studied the blocking effects of thymol and menthol on voltage-activated sodium currents in vitro as possible molecular target sites. METHODS: Whole cell sodium inward currents via heterologously (HEK293 cells) expressed rat neuronal (rat type IIA) and human skeletal muscle (hSkM1) sodium channels were recorded in the absence and presence of definite concentrations of either thymol or menthol. RESULTS: When depolarizing pulses to 0 mV were started from a holding potential of -70 mV, half-maximum blocking concentrations (IC50) for the skeletal muscle and the neuronal sodium channel were 104 and 149 mumol for thymol and 376 and 571 mumol for menthol. The blocking potency of both compounds increased at depolarized holding potentials with the fraction of inactivated channels. The estimated dissociation constant Kd for thymol and menthol from the inactivated state was 22 and 106 mumol for the neuronal and 23 and 97 mumol for the skeletal muscle sodium channel, respectively. CONCLUSIONS: The results suggest that antinociceptive and local anaesthetic effects of thymol and menthol might be mediated via blockade of voltage-operated sodium channels with the phenol derivative thymol being as potent as the local anaesthetic lidocaine.
1. Concentration-dependent effects of thymol (1 - 1000 microM) was studied on action potential configuration and ionic currents in isolated canine ventricular cardiomyocytes using conventional microelectrode and patch clamp techniques. 2. Low concentration of thymol (10 microM) removed the notch of the action potential, whereas high concentrations (100 microM or higher) caused an additional shortening of action potential duration accompanied by progressive depression of plateau and reduction of V(max). 3. In the canine cells L-type Ca current (I(Ca)) was decreased by thymol in a concentration-dependent manner (EC(50): 158+/-7 microM, Hill coeff.: 2.96+/-0.43). In addition, thymol (50 - 250 microM) accelerated the inactivation of I(Ca), increased the time constant of recovery from inactivation, shifted the steady-state inactivation curve of I(Ca) leftwards, but voltage dependence of activation remained unaltered. Qualitatively similar results were obtained with thymol in ventricular myocytes isolated from healthy human hearts. 4. Thymol displayed concentration-dependent suppressive effects on potassium currents: the transient outward current, I(to) (EC(50): 60.6+/-11.4 microM, Hill coeff.: 1.03+/-0.11), the rapid component of the delayed rectifier, I(Kr) (EC(50): 63.4+/-6.1 microM, Hill coeff.: 1.29+/-0.15), and the slow component of the delayed rectifier, I(Ks) (EC(50): 202+/-11 microM, Hill coeff.: 0.72+/-0.14), however, K channel kinetics were not much altered by thymol. These effects on Ca and K currents developed rapidly (within 0.5 min) and were readily reversible. 5. In conclusion, thymol suppressed cardiac ionic channels in a concentration-dependent manner, however, both drug-sensitivities as well as the mechanism of action seems to be different when blocking calcium and potassium channels.
The release of chlorhexidine and/or thymol from an antimicrobial containing varnish in an in vitro model was investigated. Four varnishes with the same polymer base were studied; one with chlorhexidine only, one with thymol only, one with both agents and a placebo varnish without the active agents. Microscope glass slides were covered with the varnishes and stored in water. During the following three months liquid samples were regularly withdrawn and analysed for chlorhexidine and thymol content. The released amounts of chlorhexidine and/or thymol were determined by means of U.V. spectrophotometry. The results showed that chlorhexidine was released slowly from the chlorhexidine-only varnish compared with the thymol release from the thymol-only varnish. In the case of the clinically tested varnish (containing both active ingredients chlorhexidine and thymol) the amounts of thymol and chlorhexidine released were comparable. Most important, however, was the observation that in the last mentioned case both agents continued to be released after 3 months.
The protective action of thymol (paramethyl-isopropyl-phenol) was investigated against carbon tetrachloride (CCl(4))-induced hepatotoxicity in male Swiss albino mice. The CCl(4)at a dose of 20 microl kg(-1)produced damage to liver cells and was followed by the significant increase (P<0.001) in serum alanine aminotransferase (ALT) activity and hepatic lipid peroxidation after 24 h. The hepatocellular necrosis was further confirmed by histopathological examination of liver section. Oral administration of thymol in a single dose (300 mg kg(-1)) resulted in significant (P<0.05) amelioration of CCl(4)-induced hepatotoxicity. Thymol also inhibited lipid peroxidation induced by CCl(4)in vivo. The protection offered by thymol was also evident from histopathology photomicrograph. In a separate in vitro assay, thymol inhibited the non-enzymatic lipid peroxidation of normal mice liver homogenate induced by Fe(3+)-ascorbate. The present study suggests that thymol protects the liver against CCl(4)-induced toxicity and the protection may be mediated through its ability to inhibit lipid peroxidation. However, other interactions between thymol and CCl(4)remains to be elucidated. 1999 Academic Press.
Several effects of thymol, a plant-derived antimicrobial agent, on Porphyromonas gingivalis, Selenomonas artemidis and Streptococcus sobrinus were examined. The extremely rapid efflux of intracellular constituents evoked by thymol is consistent with its postulated membranotropic effects. Correlations between leakage-inducing concentrations of thymol and minimal inhibitory concentrations and minimal bactericidal concentrations suggest that membrane perforation is a principal mode of action of this substance. The thymol-induced decline in intracellular ATP in S. sobrinus appears to be entirely attributable to leakage, whereas in P. gingivalis thymol may also inhibit ATP-generating pathways. Relative changes in the transmembrane potential of resting cells of S. sobrinus pulsed with glucose are as sensitive to thymol as is leakage from this organism. The effects of thymol on transmembrane potential are probably secondary to those arising from leakage of intracellular substances.
The properties and mechanisms of Ca release induced by thymol from the intracellular Ca-store in the guinea-pig taenia caecum were investigated and compared with those by carbachol, using an intact muscle and a microsomal fraction. In Ca, Na-free, EGTA-containing K-solution, a transient contraction was evoked by each drug, and carbachol produced the contraction following treatment with thymol; however, a reversed sequence did not. The efflux of preloaded 45Ca in the presence and absence of ATP from taenia microsomes was accelerated by increasing concentrations of Ca ions outside. The minimal concentration to stimulate 45Ca-efflux was below 0.2 microM in both cases, and the Km values for Ca ions in the presence and absence of ATP were estimated to be 0.65 microM and 2.0 microM Ca ions, respectively. Thymol, which has been reported to be one of the most potent stimulators of the Ca-induced Ca release in the sarcoplasmic reticulum of skeletal muscle, enhanced the 45Ca-efflux from the taenia microsomes in the presence of ATP dose-dependently, and its mode of action seemed bimodal. That is, at 0.5 mM, thymol lowered the concentration of Ca ions which are needed to induce stimulation of 45Ca-efflux, whereas, at 1 mM, the stimulative effect of thymol on 45Ca-efflux was to augment the maximum rate of 45Ca-efflux, independent of concentrations of Ca ions. Carbachol (1 mM) did not have an effect on 45Ca-efflux with or without 0.1 mM GTP. In conclusion, the possibility has been suggested that in the guinea-pig taenia caecum, carbachol might release stored Ca ions via unknown pathway(s), whereas thymol directly releases Ca ions in a ATP-regulated fashion. Further, carbachol would be more efficacious for releasing stored Ca ions. Notwithstanding, the Ca-stores and/or the Ca-releasing mechanisms, which are utilized by both thymol and carbachol, seemed to share a common part(s) to some degree.
In the present work we studied the antifungal effect of eugenol and thymol on the growth and production of citrinin from Penicillium citrinum (NRRL 2274 and NRRL 2269) in culture media and in different Spanish cheeses (Arzúa-Ulloa, Cebreiro and San Simón). The rate of growth was assessed by measuring colony diameters and the production of citrinin was measured using a rapid semi-quantitative fluorometric technique confirmed by RP-HPLC. A stronger inhibitory effect of eugenol than thymol was evident. 200 microg/ml of eugenol in solid culture medium increased the lag time of growth up to 9 days, and decreased the rate of colony growth. In liquid medium, a complete inhibition of fungal growth was observed. By contrast, thymol in the liquid culture medium only affected the growth rate. In Arzúa-Ulloa cheese, 200 microg/ml of eugenol fully inhibited fungal growth, while in Cebreiro cheese no effect was observed for this compound. Regarding the capacity to inhibit mycotoxin production 100 microg/ml eugenol delayed citrinin production until the sixth day, after which a limiting effect persisted. In Arzúa-Ulloa cheese, no citrinin was detected at a concentration of 150 microg/ml of eugenol, but citrinin was detected after 5 days in the case of thymol at the same concentration. In Cebreiro cheese, neither eugenol nor thymol prevented the production of citrinin at the concentrations applied.