Spectrophotometric investigation of the binding of vitamin E to water-containing reversed micelles

The distribution constants of vitamin E partitioned between apolar organic phase and water-containing reversed micelles of sodium bis (2-ethylhexyl) sulfosuccinate (AOT), didodecyldimethylammonium bromide (DDAB), soybean phosphatidylcholine (lecithin) and tetraethylene glycol monododecyl ether (C12E4) have been evaluated by a spectrophotometric method. The results suggest that in the presence of domains from apolar organic solvent to surfactant and to water, vitamin E is partitioned between the micellar palisade layer and the organic solvent and also that its binding strength to reversed micelles depends mainly by specific interactions between the head group of vitamin E and that of the surfactant. Moreover, in addition to the advantageous interactions between vitamin E and water, the dependence of the distribution constants upon the molar ratio R (R=[water]/[surfactant]) indicates a competition between water and vitamin E for the binding sites at the water/surfactant interface. The biological implications of the preferential location and confinement of vitamin E in water-containing reversed micelles are discussed.     

Effect of dimethylsulfoxide and its homologues on the thermal denaturation of lysozyme as measured by differential scanning calorimetry

The thermal denaturation of lysozyme in aqueous sulfoxide solutions (pH 3) was investigated by differential scanning calorimetry (DSC). The sulfoxides employed were dimethylsulfoxide (DMSO), ethylmethylsulfoxide (EMSO), diethylsulfoxide (DESO), and butylmethylsulfoxide (BMSO). The temperature of denaturation, T_d, decreased with an increase in the concentration of sulfoxide, the decrease becoming much more pronounced at higher sulfoxide concentrations. The lowering of T_d was enhanced by an increase in the hydrocarbon content of the sulfoxide molecule. The enthalpy of denaturation, ΔH_d, showed a complex dependence on the solvent composition; the ΔH_d first increased with increasing sulfoxide concentration and then started decreasing at different concentrations for each sulfoxide. This behavior is analogous to that with monohydric alcohols, but is different from that with guanidine hydrochloride. These results may be interpreted in terms of the interactions of the sulfoxide added with the protein and with water.     

Characterization and comparison of leuprolide degradation profiles in water and dimethyl sulfoxide

Abstract: The effect of solvent on the rate of leuprolide degradation and on the structure of the degradation products was explored. Leuprolide solutions (370 mg/mL) were prepared in water and dimethyl sulfoxide (DMSO) for delivery in DUROS^TM osmotic implants. Both solvent systems demonstrated better than 90% stability after 1 year at 37°C, where the DMSO formulation afforded better stability than the aqueous formulation and was used in subsequent clinical trials. The rate of leuprolide degradation in DMSO was also observed to accelerate with increasing moisture content, indicating that the aprotic solvent minimized chemical degradation. Interestingly, leuprolide degradation products varied with formulation vehicle. The proportions of leuprolide degradation products observed to form in water and DMSO at 37°C were hydrolysis > aggregation > isomerization > oxidation and aggregation > oxidation > hydrolysis > isomerization, respectively. Specifically, more N-terminal hydrolysis and acetylation were observed under aqueous conditions, and increased Trp oxidation and Ser β-elimination were seen under non-aqueous conditions. Furthermore, the major chemical degradation pathway changed with temperature in the DMSO formulation (decreasing oxidation with increasing temperature), but not in the aqueous formulation.     

Prevention of acetaminophen-induced hepatotoxicity by dimethyl sulfoxide

Dimethyl sulfoxide (DMSO) has previously been shown to protect against acetaminophen (APAP)-induced hepatotoxicity, but the mechanism of this effect was not clear. Treatment of mice with 1 mg/kg DMSO 4 h before 250 mg/kg APAP resulted in significantly less hepatotoxicity than with APAP alone, as measured by serum glutamic pyruvic transaminase (SGPT) content 24 h after APAP. Protection was also evident when 1 ml/kg DMSO was given 4, but not 8 h after 250 mg/kg APAP. The APAP-induced depletion of liver glutathione was prevented in mice pretreated with DMSO, although DMSO alone had no effect on liver glutathione levels. The hepatic concentration of cytochrome P-450 (P450) 4 h after treatment of mice with 1 ml/kg DMSO, was significantly decreased compared to saline-treated animals. However, while this DMSO pretreatment significantly decreased the activity of cytochrome P-450-linked aminopyrine-N-demethylase, it increased the activity of aniline hydroxylase. Covalent binding of [14C]APAP to hepatic protein in vivo was significantly decreased in mice pretreated with DMSO. Covalent binding of [14C]APAP to hepatic microsomal protein in vitro was not significantly altered after in vivo treatment with DMSO. However, the presence of DMSO in the in vitro incubation mixture significantly decreased covalent binding of [14C]APAP in a dose-dependent manner compared to microsomal fractions from untreated, saline-treated or DMSO pretreated animals. These data suggest that the DMSO-induced alterations in cytochrome P-450 content and activity may not be the cause of the observed protective action of this chemical. The ability to competitively inhibit APAP bioactivation or to directly scavenge free radicals produced during APAP metabolism, including the activated species which covalently binds to protein, may account for the hepatoprotection afforded by DMSO.     

Inhibition of sulindac metabolism by dimethyl sulfoxide in the rat

Dimethyl sulfoxide (DMSO) suppresses conversion of the prodrug sulindac to its bioactive sulfide metabolite (SD) by competitively inhibiting sulfoxide reductase. During continuous iv infusions of sulindac (1 mg/kg X h), plasma concentrations of SD at steady-state equilibrium were 80% lower when DMSO was infused concomitantly at 0.34 ml/kg X h, whereas sulindac plasma concentrations were not significantly affected by DMSO. Dermal application and intragastric administration of DMSO also inhibited SD accumulation in plasma. DMSO was only a weak inhibitor of SD oxidation in vitro and did not affect the rate of SD elimination in vivo. In contrast, dimethyl sulfide, a metabolite of DMSO, was a potent inhibitor of SD oxidase in vitro. These data suggest that DMSO can inhibit bioactivation and, hence, the antiinflammatory effects of sulindac.     

Stimulatory and inhibitory effects of dimethyl sulfoxide on microsomal aniline hydroxylase activity

Dimethyl sulfoxide (DMSO) at a single dose of 3 ml/kg body wt, administered i.p. to male rats, caused a significant increase in the hepatic microsomal aniline hydroxylase activity. However, the level of cytochrome P-450, the activities of NADPH-cytochrome c reductase, benzphetamine N-demethylase and aminopyrine N-demethylase were unchanged at 24 h post-treatment. DMSO interacted with control rat liver microsomes in vitro and produced a type II spectral change (peak at 420 nm and trough at 392 nm). On the other hand, liver microsomes from DMSO-treated rats gave qualitatively similar spectra, but with a higher magnitude of binding. Liver microsomes from DMSO-treated rats showed a 3.4-fold increase in Vmax for aniline hydroxylase, while Km was found to be the same when compared with control rat liver microsomes. In vitro addition of 6 mM DMSO to microsomal incubations from control and DMSO-treated rats caused a 9-fold and a 25-fold increase in Km, respectively, while Vmax values for aniline hydroxylase were unchanged. When DMSO (6 mM) was incubated with rat liver microsomes in the presence of NADPH, there was formation of formaldehyde. The results suggest an interaction of DMSO with microsomal cytochrome P-450.     

Anti-angiogenic effects of dimethyl sulfoxide on endothelial cells

Dimethyl sulfoxide (DMSO) has anti-inflammatory and analgesic properties and is the only intravesical agent approved by the FDA for the treatment of interstitial cystitis. While it is known that DMSO has numerous biological effects on cell differentiation and alteration of cell-surface carbohydrate structures, the anti-inflammatory mechanism of DMSO has been not clear yet. Therefore, further investigation of DMSO in terms of inflammation therapy is needed. This study assessed the in vitro anti-angiogenic effects of DMSO on human aorta endothelial cells to clarify one of the mechanisms of its anti-inflammatory activity. DMSO did not affect expression of E-selectin on endothelial cells in the presence of TNF-alpha. Furthermore, DMSO effectively inhibited capillary tube formation; this mechanism would be due to suppression of matrix metalloproteinase-2 (MMP-2) production. These results provide useful knowledge about the anti-inflammatory effects of DMSO and the regulatory mechanism of MMP-2.     

Failure of dimethyl sulfoxide (DMSO) to alter thyroid function in the Sprague-Dawley rat

Male Sprague-Dawley rats 60 days and 1 year of age were injected with 63% or 85% dimethyl sulfoxide (DMSO) and several phases of thyroid function examined. Iodide transport was not affected by injection of either 63% or 85% DMSO. There was no significant difference between the saline-injected and DMSO-injected groups in the thyroid: serum radioiodide concentration ratios (T:S). The response of the thyroid gland to the injection of an acute substantial iodide load was unaltered by prior injection of 85% DMSO. The inhibition in glandular binding of iodide was similar in both saline-injected and DMSO-injected groups as evidenced by the thyroidal accumulation of newly formed organic iodine and thyroidal concentration of iodide. Chromatographic analyses of thyroid pronase hydrolyzates in saline-injected and DMSO-injected rats revealed a similar reduction in labeling of iodothyronines, an increase in the fraction of labeled iodide, an increase in thyroidal labeling of MIT with consequent elevation in ratio of [¹³¹I] MIT:DIT. The radioiodine release rate was also not affected by injection of DMSO or dermal application of DMSO. Present results indicate that DMSO was not effective in influencing thyroid function in the rat.     

The prevention of alloxan-induced diabetes in mice by dimethyl sulfoxide

Dimethyl sulfoxide (DMSO, 7.3 g/kg) administered to mice prior to alloxan completely protected against the diabetogenic actions of 50 mg/kg alloxan. The same dose of DMSO provided a partial protection against 75 mg/kg alloxan. This protection against alloxan-induced diabetes is consistent with the scavenging of the hydroxyl radical by DMSO.     

Inhibition of alcohol dehydrogenase by dimethyl formamide and dimethyl sulfoxide

Dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO) inhibit mouse liver alcohol dehydrogenase (LADH) in vitro. The inhibition is “uncompetitive” with both DMF and DMSO, where both Km and Vmax were changed in the presence of the inhibitor. Both DMF and DMSO prolonged significantly ethanol-induced loss of righting reflex in mice, but not barbital-induced loss of righting reflex.     

Dimethyl sulfoxide (DMSO)--an overview.

The solvent dimethyl sulfoxide (DMSO) has received intense lay publicity sporadically over the last two decades. The compound has been particularly promoted as an analgesic and anti-inflammatory agent. Its membrane penetrant-carrier properties have also been of prime interest. The history, physical/chemical and pharmacological properties, pharmacokinetics, clinical trials, therapeutic uses, side effects and dosage/administration of DMSO are reviewed. Legal implications and concerns with regard to DMSO use are presented in addition to advice for patients.     

Dimethyl sulfoxide: recent pharmacological and toxicological research

A survey of the literature published in the past 2 decades on the basic pharmacology, therapeutic uses and toxicity of dimethyl sulfoxide (DMSO) is presented. A salient pharmacological action of DMSO is its ability to scavenge oxygen-free radicals implicated in xenobiotic-induced tissue damages when given before, during or several hours after the tissue insult. More trials with DMSO in diseases and conditions caused by oxygen-free radicals are warranted.     

Evaluation of the genotoxic potential of dimethyl sulfoxide (DMSO) in meristematic cells of the root of Vicia faba

Dimethyl sulfoxide (DMSO) is an organic solvent with several biological applications. It is extensively used to dissolve compounds that hardly dissolve in water to detect their genotoxic activity in vitro. In this study DMSO will be tested to determine its genotoxic potential. The effect of DMSO on the frequency of chromosomal aberrations in anaphase as well as DNA fragmentation through the comet assay has been evaluated in the meristematic cells of the root tips of Vicia faba. It has been observed that the frequency of chromosomal aberrations increases when the concentration of DMSO increases, reaching its maximum value with 20% of DMSO and decreasing at 30 and 40% of DMSO, in comparison to this maximum value, but significantly higher than the values observed in the control. Similarly, the percentage of fragmentation and damage index evaluated through the comet assay showed the same behavior; some of the possible mechanisms of action are discussed.     

The actions of dimethyl sulfoxide on neuromuscular transmission

The effects of dimethyl sulfoxide (DMSO) on subsynaptic response and quantal release of transmitter have been studied at the mammalian neuromuscular junction. Subsynaptically, at low concentrations (up to 1% by volume), DMSO prolongs the time course of decay of miniature endplate currents, (MEPCs), with no significant effect on the amplitude of the currents, which is consistent with an action of DMSO to inhibit acetylcholinesterase. At higher concentrations of DMSO (in excess of 1% by volume) the amplitude of MEPCs and the steady state response to carbamoylcholine (carbachol) are significantly reduced, which suggests an additional action of DMSO other than pure anticholinesterase activity. After pretreatment of the preparation with a low concentration of paraoxon, higher concentrations of DMSO decrease MEPC height and cause highly variable changes in the decay time course of the MEPC. The results suggest that DMSO concentrations in excess of 1% by volume have two distinct and opposite actions on the subsynaptic response; a pure anticholinesterase activity to enhance the response and a depressant effect which is similar to that caused by d-tubocurarine. Presynaptically, DMSO increased both the spontaneous release (measured as the frequency of miniature endplate potentials, fMEPP) and the evoked release (measured as the quantal content of endplate potentials). Both types of release were increased as an exponential function, with the same slope, of the DMSO concentration, suggesting a common mode of action on these two types of release. This action appeared not to be due to an effect on the disposition or effectiveness of calcium ions inside the terminal but, rather, was due to a fusogenic or global effect. In addition, the increase in fMEPP with DMSO was the same when external calcium was replaced by barium. At the concentrations studied, up to 8% by volume, DMSO did not cause any substantial depolarization of the nerve terminal or any appreciable change in the nerve terminal action potential. In a few experiments facilitation was studied at the frog neuromuscular junction and was unchanged by DMSO at concentrations which considerably enhanced transmitter release.     

Hepatoprotection by dimethyl sulfoxide. III. Role of inhibition of the bioactivation and covalent bonding of chloroform

Dimethyl sulfoxide (DMSO) has previously been shown to have the ability to attenuate chloroform (CHCl(3))-induced liver injury in the naive rat even when administered 24 h after the toxicant. These studies were undertaken to determine if the protective action by late administration of DMSO is due to an inhibition of the bioactivation of CHCl(3). This was done by comparing the cytochrome P450 inhibitors, diallyl sulfide (DAS), and aminobenzotriazole (ABT) to DMSO for their protective efficacy when administered 24 h after CHCl(3) exposure. In addition, (14)CHCl(3) was utilized to measure the effect of DMSO and ABT on the covalent binding of CHCl(3) in the liver following their late administration. Male Sprague-Dawley rats (300-350 g) received 0.75 ml/kg CHCl(3) po. Twenty-four hours later, they received ip injection of 2 ml/kg DMSO, 100 mg/kg DAS, or 30 mg/kg ABT. Plasma ALT activities and quantitation of liver injury by light microscopy at 48 h after CHCl(3) dosing indicated that all three treatments were equally effective at protecting the liver. A detailed study of the time course of injury development indicated that the protective action of DMSO was occurring within 10 h of its administration. Therefore, in the radiolabel studies, rats were killed 24-34 h after receiving 0.75 ml/kg CHCl(3) (30 microCi/kg (14)CHCl(3)) po. Treatment with ABT at 24 h after (14)CHCl(3) dosing decreased the covalent binding of (14)C to hepatic protein by 35% and reduced the amount of (14)C in the blood by 50% by 10 h after its administration. DMSO treatment did not significantly affect any of these parameters. The lack of effect by late administration of DMSO on the covalent binding of CHCl(3) would indicate that DMSO may offer protection by mechanisms other than inhibition of the bioactivation of CHCl(3). These studies also indicate that specific cytochrome P450 inhibitors may be of benefit in clinical situations to help treat the delayed onset hepatitis that can result following poisoning with an organohalogen, even if the antidotes are administered a number of hours after the initial exposure.     

A comparative study of antioxidants S-allyl cysteine sulfoxide and vitamin E on the damages induced by nicotine in rats

The dietary consumption of antioxidant-rich fruits and vegetables is inversely correlated with the incidence of various diseases like cardiovascular diseases and lung cancer. We have tried to find out how far the S-allyl cysteine sulfoxide (SACS) isolated from garlic (Allium Sativum L.) can combat the nicotine-induced peroxidative damage in rats. The effects have been compared with the standard antioxidant vitamin E. Administration of SACS or vitamin E (100 mg/kg) to nicotine (0.6 mg/kg) treated rats for 21 days showed decreased concentrations of thiobarbituric acid reactive substances, hydroperoxides, and conjugated dienes in liver, lungs, and heart as compared with the values found in rats treated with nicotine alone. The activities of catalase and superoxide dismutase increased. The levels of the antioxidants like vitamins A, C, and E in the liver and glutathione in all tissues increased significantly in SACS-treated or vitamin E fed rats. However, the antioxidant status was higher when vitamin E was administered as compared with SACS administered to nicotine-treated rats.     

Novel polymer micelles prepared from chitosan grafted hydrophobic palmitoyl groups for drug delivery

Chitosan-based polymer micelles have a splendid outlook for drug delivery owing to the interesting properties, abundance, and low cost of chitosan. A new method of preparation of water-soluble N-palmitoyl chitosan (PLCS) which can form micelles in water is developed in this paper. The preparation of PLCS was carried out by swollen chitosan coupling with palmitic anhydride in dimethyl sulfoxide (DMSO). The degree of substitution (DS) of PLCS was in the range of 1.2-14.2%, and the critical aggregation concentration (CAC) of PLCS micelles was in the range of 2.0 x 10(-3) to 37.2 x 10(-3) mg/mL. The properties of PLCS micelles such as encapsulation capacity and controlled release ability of hydrophobic model drug ibuprofen (IBU) were evaluated. Experimental results indicated that the loading capacity (LC) of PLCS was approximately 10%. The drug release strongly depended on pH and temperature: low pH and high temperature accelerated drug release markedly. Moreover, the IR, 1H NMR, and TEM of PLCS, IBU-loaded PLCS, and a PLCS-IBU physical mixture have been measured to show that IBU is loaded by PLCS micelles.     

Enhanced production of microbial metabolites in the presence of dimethyl sulfoxide

Bacterial strains grown in the presence of low concentrations of dimethyl sulfoxide (DMSO) exhibit significant qualitative and quantitative alterations in the production of secondary metabolites. This effect was confirmed for a variety of biosynthetic families, including chloramphenicol (chorismate), thiostrepton (peptide) and tetracenomycin (polyketide), and for natural and recombinant strains of streptomycetes; a similar effect was seen with antibiotic-producing bacilli such as B. circulans. Increase in antibiotic production was not the result of a change in the growth rate of these organisms, since yields of biomass were similar in media with and without DMSO (up to 3%). We suggest that the addition of compounds such as DMSO provides a means of examining the full biosynthetic potential of microbes and might be used to promote secondary metabolite production. The mode of action of DMSO is not known, but in the cases studied it may act at the level of translation.     

Dimethyl sulfoxide effects on hERG channels expressed in HEK293 cells

INTRODUCTION: Dimethyl sulfoxide (DMSO) is widely used as a solvent to facilitate formulation of test substances in cell perfusion solutions. However, DMSO concentration in bath (extracellular) solution is usually limited to 0.1-0.3% to avoid DMSO-induced changes in cell morphology and membrane properties due to elevation of osmolality. The purpose of this study was to examine whether DMSO-induced hyperosmotic effects on hERG expressing cells could be compensated by adding an equivalent amount of DMSO in pipette (intracellular) solution, to investigate DMSO effects on hERG channels, and to determine the impact of DMSO on the potency of hERG channel blockers. METHOD: Whole-cell patch clamp method was used to record hERG currents in HEK293 cells. DMSO at concentrations of 0.1% to 2% was applied to bath and pipette solutions. Various voltage protocols were used to examine DMSO effects on hERG channel properties and to evaluate DMSO impacts on the potency of terfenadine and E-4031. RESULTS: When DMSO was added simultaneously in bath and pipette solutions, normal cell morphology and the proper current recording conditions could be maintained with application of up to 2% DMSO. DMSO slightly shifted the current-voltage relationship, activation curve, and inactivation curve of the hERG channel to more positive voltages. DMSO had little effect on the concentration-response relationship of hERG channel blockers we assessed. The IC50 for terfenadine and E-4031 were not significantly changed in the presence of 0.3, 0.5, 1 and 2% DMSO. DISCUSSION: Our results demonstrate that changes in cell morphology induced by extracellular DMSO can be prevented by application of DMSO in pipette solution. By utilizing this approach, we successfully performed hERG current recordings using bath solution containing up to 2% DMSO. DMSO-induced shifts of the voltage-dependence of hERG channel gating had little impact on the potency of hERG channel blockers.     

反胶束体系的组成对胆甾醇酯酶催化水解维生素E醋酸酯活性的影响

目的考察反胶束体系的组成对胆甾醇酯酶催化水解维生素E醋酸酯活性的影响。方法以卵磷脂、聚乙二醇对辛基苯基醚为表面活性剂 ,以溶有维生素E醋酸酯的不同有机溶剂为油相制备不同反胶束溶液 ,将胆甾醇酯酶溶入制得的反胶束体系使维生素E醋酸酯水解 ,采用HPLC法测定水解产物维生素E的生成量。结果有机溶剂、体系含水量、表面活性剂和助表面活性剂及其配比对反胶束体系中酶的活性影响较大。结论 14mmol·L-1卵磷脂 6mmol·L-1胆固醇 环已烷反胶束体系 (W0 =10 5 )是胆甾醇酯酶催化水解维生素E醋酸酯的最佳反应介质