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PubMed1996

Degradation of Toluene and Trichloroethylene by Burkholderia cepacia G4 in Growth-Limited Fed-Batch Culture.

Burkholderia (Pseudomonas) cepacia G4 was cultivated in a fed-batch bioreactor on either toluene or toluene plus trichloroethylene (TCE). The culture was allowed to reach a constant cell density under conditions in which the amount of toluene supplied equals the maintenance energy demand of the culture. Compared with toluene only, the presence of TCE at a toluene/TCE ratio of 2.3 caused a fourfold increase in the specific maintenance requirement for toluene from 22 to 94 nmol mg of cells (dry weight)(sup-1) h(sup-1). During a period of 3 weeks, approximately 65% of the incoming TCE was stably converted to unidentified products from which all three chlorine atoms were liberated. When toluene was subsequently omitted from the culture feed while TCE addition continued, mutants which were no longer able to grow on toluene or to degrade TCE appeared. These mutants were also unable to grow on phenol or m- or o-cresol but were still able to grow on catechol and benzoate. Plasmid analysis showed that the mutants had lost the plasmid involved in toluene monooxygenase formation (pTOM). Thus, although strain G4 is much less sensitive to TCE toxicity than methanotrophs, deleterious effects may still occur, namely, an increased maintenance energy demand in the presence of toluene and plasmid loss when no toluene is added.

Journal Article↗
PubMed1997

Teratogen update: toluene.

Extrapolating from animal data, at the level at which well-controlled occupational exposure to toluene vapor is encountered, in utero exposure does not pose a significant fetal risk. However, following chronic and excessive industrial accidents or intentional abuse, toluene exposure several orders of magnitude greater exists, and at these levels in utero exposures in both animals and humans have been shown to produce significant delays in fetal growth. At these greater exposure levels, both dose and gestational timing relationships can be demonstrated in animal models. Of note, in both animals and humans, postnatal persistence of growth deficiency has been observed. A pattern of teratogenicity similar to that of the fetal alcohol syndrome is prevalent in all human studies of excessive in utero exposure to toluene. In humans, the effects of in utero toluene exposure among intentional abusers is confounded by such variables as general health and exposure to other teratogens. Chronic toluene abuse produces a renal tubular acidosis with maternal hypokalemia and profoundly lowered serum pH. Further evaluation of greater numbers of infants with respect to maternal renal tubular acidosis will be needed to fully assess the contribution of chronic acidosis. The contribution of maternal acidosis to fetal teratogenicity remains speculative. Coabuse of additional agents, in particular alcohol, may increase the teratogenic risks. The overlap of features following in utero toluene abuse with those of fetal alcohol syndrome suggests a possible common pathway of craniofacial teratogenesis. Lastly, genetic variations that result in deficiency of ALDH2, an enzyme involved in toluene metabolism, may increase the risks of toluene teratogenicity in at-risk individuals at lower levels of exposure. Prospective studies of toluene-exposed pregnancies would provide more information on the fetal effects at these levels.

Abnormalities, Drug-Induced↗
PubMed2000

Kinetic analysis of a tod-lux bacterial reporter for toluene degradation and trichloroethylene cometabolism.

Kinetics of toluene and trichloroethylene (TCE) degradation and bioluminescence from the bioreporter Pseudomonas putida B2 and TVA8 were investigated utilizing batch and continuous culture, respectively. Degradation was modeled using a Michaelis-Menten expression for the competition of two substrates for a single enzyme system, and bioluminescence was modeled assuming a luciferase enzyme saturational dependence on toluene as the inducer and growth substrate. During the batch experiments, bioluminescence increased at approximately 90 namp/min for initial toluene concentrations of 10 to 50 mg/L, but more slowly at higher toluene concentrations, suggesting maximum promoter induction at below 10 mg/L and toxic effects above 50 mg/L toluene. TCE degradation did not occur until toluene depletion, presumably due to competition between toluene and TCE for the toluene dioxygenase enzyme. During continuous culture, bioluminescence transiently increased, then gradually decreased in response to increasing step changes in toluene feed concentration. Bioluminescence in the CSTR appeared to be limited by growth substrate and/or inducer.

Biodegradation, Environmental↗
PubMed2004

Effect of ethanol, acetate, and phenol on toluene degradation activity and tod-lux expression in Pseudomonas putida TOD102: evaluation of the metabolic flux dilution model.

The reporter strain Pseudomonas putida TOD102 (with a tod-lux fusion) was used in chemostat experiments with binary substrate mixtures to investigate the effect of potentially occurring cosubstrates on toluene degradation activity. Although toluene was simultaneously utilized with other cosubstrates, its metabolic flux (defined as the toluene utilization rate per cell) decreased with increasing influent concentrations of ethanol, acetate, or phenol. Three inhibitory mechanisms were considered to explain these trends: (1) repression of the tod gene (coding for toluene dioxygenase) by acetate and ethanol, which was quantified by a decrease in specific bioluminescence; (2) competitive inhibition of toluene dioxygenase by phenol; and (3) metabolic flux dilution (MFD) by all three cosubstrates. Based on experimental observations, MFD was modeled without any fitting parameters by assuming that the metabolic flux of a substrate in a mixture is proportional to its relative availability (expressed as a fraction of the influent total organic carbon). Thus, increasing concentrations of alternative carbon sources "dilute" the metabolic flux of toluene without necessarily repressing tod, as observed with phenol (a known tod inducer). For all cosubstrates, the MFD model slightly overpredicted the measured toluene metabolic flux. Incorporating catabolite repression (for experiments with acetate or ethanol) or competitive inhibition (for experiments with phenol) with independently obtained parameters resulted in more accurate fits of the observed decrease in toluene metabolic flux with increasing cosubstrate concentration. These results imply that alternative carbon sources (including inducers) are likely to hinder toluene utilization per unit cell, and that these effects can be accurately predicted with simple mathematical models.

Acetic Acid↗
PubMed1997

The central nervous system and exposure to toluene: a risk characterization.

The principal health outcome of exposure to toluene is dysfunction of the central nervous system. Effects range from fatalities and severe neurological disorders in toluene abuse situations to deficits in neurobehavioral function in occupational populations. An Inhalation Reference Concentration (RfC) of 0.4 mg toluene/m3 or 0.1 ppm was developed by the U.S. EPA to protect general populations chronically exposed to toluene. The RfC was derived from results of an occupational study involving Asian workers who developed neurobehavioral deficits at a mean toluene exposure level at the time of the study of 88 ppm. The derivation incorporated several uncertainty factors, one of which was a factor of 10 to account for sensitive subpopulations. Recent evidence indicates that some Japanese and possibly other Asian populations harbor a defective gene for aldehyde dehydrogenase, and thus exhibit a decreased rate of toluene metabolism. Although it is not known if reduced metabolism by aldehyde dehydrogenase also was a factor in the occupational study, preshift blood levels of toluene were considerably higher than preshift levels from non-Asian workers exposed to similar air levels of toluene. The elevated blood levels are consistent with defective metabolism but remain to be confirmed. Inasmuch as air levels of toluene in urban environments are about 10-fold lower than the RfC, an adequate measure of protection is afforded by the RfC with or without an uncertainty factor for sensitive subgroups. However, the uncertainty factor for sensitive subgroups should be retained because there is no information regarding toluene metabolism in children.

Air Pollution, Indoor↗
PubMed1987

Effects of pretreatment of male NMRI mice with enzyme inducers or inhibitors on clastogenicity of toluene.

Five groups of young male NMRI mice were pretreated with IP injections of three known inducers of cytochrome P450, Aroclor 1254, phenobarbital and 3-methylcholanthrene, and two inhibitors, metyrapone and alpha-naphthoflavone, 5, 3, 2, 1, and 1 day(s) before receiving toluene, respectively. Toluene was given to animals by IP injections of two similar doses 24 h apart. Increased formation of micronuclei within polychromatic erythrocytes of femoral bone marrow 30 h after the first injection of toluene was recorded. None of the treatments with an inducer or inhibitor alone gave a significant increase in the frequency of micronucleated polychromatic erythrocytes. However, pretreatment of animals with each inducer or even inhibitor resulted in an enhanced clastogenic activity of toluene. Simultaneous injections of an inhibitor and toluene clearly decreased the clastogenicities observed. Enhancement of the clastogenicity of toluene was more evident among Aroclor -pretreated animals than among the other groups. Treatment of animals with a mixture of toluene and benzene did not result in an additive clastogenic activity of benzene. IP injection of a mixture of toluene and every xylene isomer resulted in an enhanced clastogenic activity of toluene, although xylene isomers are not found to be clastogenic.

Animals↗
PubMed1995

Stoichiometry and kinetics of microbial toluene degradation under denitrifying conditions.

Batch experiments were carried out to investigate the stoichiometry and kinetics of microbial degradation of toluene under denitrifying conditions. The inoculum originated from a mixture of sludges from sewage treatment plants with alternating nitrification and denitrification. The culture was able to degrade toluene under anaerobic conditions in the presence of nitrate, nitrite, nitric oxide, or nitrous oxide. No degradation occurred in the absence of Noxides. The culture was also able to use oxygen, but ferric iron could not be used as an electron acceptor. In experiments with 14C-labeled toluene, 34% +/- 8% of the carbon was incorporated into the biomass, while 53% +/- 10% was recovered as 14CO2, and 6% +/- 2% remained in the medium as nonvolatile water soluble products. The average consumption of nitrate in experiments, where all the reduced nitrate was recovered as nitrite, was 1.3 +/- 0.2 mg of nitrate-N per mg of toluene. This nitrate reduction accounted for 70% of the electrons donated during the oxidation of toluene. When nitrate was reduced to nitrogen gas, the consumption was 0.7 +/- 0.2 mg per mg of toluene, accounting for 97% of the donated electrons. Since the ammonia concentration decreased during degradation, dissimilatory reduction of nitrate to ammonia was not the reductive process. The degradation of toluene was modelled by classical Monod kinetics. The maximum specific rate of degradation, k, was estimated to be 0.71 mg toluene per mg of protein per hour, and the Monod saturation constant, Ks, to be 0.2 mg toluene/l. The maximum specific growth rate, mu max, was estimated to be 0.1 per hour, and the yield coefficient, Y, was 0.14 mg protein per mg toluene.

Bacteria, Anaerobic↗
PubMed2006

Metabolic correlates of toluene abuse: decline and recovery of function in adolescent animals.

RATIONALE: Children and adolescents will readily abuse household products that contain solvents such as toluene. It is likely that reinforcing exposures to toluene alter brain glucose metabolism. OBJECTIVE: Using an animal model of drug reinforcement, we sought to identify a metabolic signature of toluene abuse in the adolescent rodent brain. Small animal PET (microPET), in combination with the glucose analog radiotracer, (18)FDG, were used to evaluate the metabolic consequences of inhaled toluene. METHODS: The exposure protocol paralleled our previously established method for assessing the conditioned reinforcing effects of toluene (5,000 ppm) using the conditioned place preference (CPP) paradigm. Animals were scanned at baseline and 2 h after the last exposure. Follow-up (18)FDG scans occurred 1 day, 3 weeks, and 2 months later. RESULTS: After six pairings, 38% of the animals preferred the toluene paired chamber and 25% were averse. The immediate metabolic effect in toluene-exposed animals was a 20% decline in whole brain (18)FDG uptake. Twenty-four hours following the last exposure, the whole brain decline was 40%, and 2 months later, the decline was 30% of pretoluene levels. A region-by-region analysis demonstrated significant additional decreases in the pons, cerebellum, striatum, midbrain, temporal cortex, and hippocampus. Two months after toluene cessation, regions of complete metabolic recovery were the thalamus and cerebellum; however, the temporal cortex did not recover. CONCLUSIONS: Brain uptake of (18)FDG appears to be a useful tool for examining the metabolic impact of toluene abuse, which include a profound decline followed by region-specific recovery after cessation.

Animals↗
PubMed2003

Mesophilic and thermophilic BTEX substrate interactions for a toluene-acclimatized biofilter.

Benzene, toluene, ethylbenzene and xylene (BTEX) substrate interactions for a mesophilic (25 degrees C) and thermophilic (50 degrees C) toluene-acclimatized composted pine bark biofilter were investigated. Toluene, benzene, ethylbenzene, o-xylene, m-xylene and p-xylene removal efficiencies, both individually and in paired mixtures with toluene (1:1 ratio), were determined at a total loading rate of 18.1 g m(-3) h(-1) and retention time ranges of 0.5-3.0 min and 0.6-3.8 min for mesophilic and thermophilic biofilters, respectively. Overall, toluene degradation rates under mesophilic conditions were superior to degradation rates of individual BEX compounds. With the exception of p-xylene, higher removal efficiencies were achieved for individual BEX compounds compared to toluene under thermophilic conditions. Overall BEX compound degradation under mesophilic conditions was ranked as ethylbenzene >benzene > o-xylene > m-xylene > p-xylene. Under thermophilic conditions overall BEX compound degradation was ranked as benzene > o-xylene >ethylbenzene > m-xylene > p-xylene. With the exception of o-xylene, the presence of toluene in paired mixtures with BEX compounds resulted in enhanced removal efficiencies of BEX compounds, under both mesophilic and thermophilic conditions. A substrate interaction index was calculated to compare removal efficiencies at a retention time of 0.8 min (50 s). A reduction in toluene removal efficiencies (negative interaction) in the presence of individual BEX compounds was observed under mesophilic conditions, while enhanced toluene removal efficiency was achieved in the presence of other BEX compounds, with the exception of p-xylene under thermophilic conditions.

Bacteria↗
PubMed2001

BTEX catabolism interactions in a toluene-acclimatized biofilter.

BTEX substrate interactions for a toluene-acclimatized biofilter consortium were investigated. Benzene, ethylbenzene, o-xylene, m-xylene and p-xylene removal efficiencies were determined at a loading rate of 18.07 g m(-3) h(-1) and retention times of 0.5-3.0 min. This was also repeated for toluene in a 1:1 (m/m) ratio mixture (toluene: benzene, ethylbenzene, or xylene ) with each of the other compounds individually to obtain a final total loading of 18.07 g m(-3) h(-1). The results obtained were modelled using Michaelis-Menten kinetics and an explicit finite difference scheme to generate vmax and Km parameters. The Vmax/Km ratio (a measure of the catalytic efficiency, or biodegradation capacity, of the reactor) was used to quantify substrate interactions occurring within the biofilter reactor without the need for free-cell suspended and monoculture experimentation. Toluene was found to enhance the catalytic efficiency of the reactor for p-xylene, while catabolism of all the other compounds was inhibited competitively by the presence of toluene. The toluene-acclimatized biofilter was also able to degrade all of the other BTEX compounds, even in the absence of toluene. The catalytic efficiency of the reactor for compounds other than toluene was in the order: ethylbenzene > benzene > o-xylene > m-xylene>p-xylene. The catalytic efficiency for toluene was reduced by the presence of all other tested BTEX compounds, with the greatest inhibitory effect being caused by the presence of benzene, while o-xylene and p-xylene caused the least inhibitory effect. This work illustrated that substrate interactions can be determined directly from biofilter reactor results without the need for free-cell and monoculture experimentation.

Bacteria↗
PubMed1998

Qualitative color vision impairment in toluene-exposed workers.

OBJECTIVE: The aim of this study was to evaluate whether toluene, like many other organic solvents and solvent mixtures, could impair color vision. SUBJECTS AND METHODS: We investigated color vision impairment in three groups of workers, two groups occupationally exposed to toluene and a nonexposed group. The first exposed group, group E1, comprised 41 workers (median value of toluene in air 35.00 ppm, range 11.3-49.3 ppm) and the second exposed group, group E2, comprised 32 subjects (median value of toluene in air 156.00 ppm, range 66.0-250.0 ppm). The nonexposed group, group NE, comprised 83 subjects. Color vision was evaluated by the Lanthony D-15 desaturated test according to Verriest's classification: type I, loss in the red-green range; type II, loss in the blue-yellow and red-green ranges, and type III, loss in the blue-yellow range. Subjects were classified as dyschromates if specific acquired loss was determined in at least one eye. In both exposed groups, exposure was evaluated by measurement of the concentration of toluene in the ambient air and in the blood. In group E2, level of hippuric acid and orthocresol in urine after the work shift were also determined. The Mann-Whitney U-test, t-test, chi 2-test, and Spearman's rank correlation and multiple regression analysis were used for statistical analysis. RESULTS: Type III dyschromatopsia was detected in all groups examined: 26.6% of the workers in group NE, 31.7% of those in group E1, and 50% of those in group E2. As many as 15.6% of the workers in group E2, 4.8% of those in group E1, and only 1.2% of those in group NE had type II dyschromatopsia. A statistically significant difference in the prevalence of total dyschromatopsia (type III + type II) was established among the three examined groups together (chi 2 = 14.13; df = 2; P < 0.01), between group E2 and group E1 (chi 2 = 4.96; P < 0.05), and between group E2 and group NE (chi 2 = 12.50; P < 0.005), whereas no significant difference was found between groups E1 and NE. Type III dyschromatopsia was significantly correlated with age in group NE (P < 0.01) and in group E1 (P < 0.005). In group E2, both type II (P < 0.05) and type III dyschromatopsia correlated with toluene in ambient air and with the duration of exposure to toluene (both P < 0.005). In group E2, total dyschromatopsia correlated significantly with toluene in ambient air and in blood (both P < 0.05) as well as with hippuric acid in urine after the work shift (P < 0.001). CONCLUSION: This study suggests that toluene can impair color vision.

Adult↗
PubMed2005

Effect of toluene and nutritional status on serotonin, lipid peroxidation levels and NA+/K+-ATPase in adult rat brain.

The aim was to evaluate the effect of toluene and nutritional status on levels of serotonin (5-HT), 5-hydroxytryptophan (5-HTP), Na+/K+-ATPase, total ATPase and lipid peroxidation (TBARS) in rat brain. Study was conducted with malnourished (MN), well-nourished (WN) and normal Wistar rats. Three groups were formed for each nutritional status: control group I received 0.9% NaCl; toluene (1 g/kg) was administered to group II, and 1.5 g/kg to group III. Levels of 5-HT decreased (P < 0.05) in WN toluene groups, and 5-HTP decreased (P < 0.05) in the WN 1 g toluene and MN 1.5 g toluene groups. TBARS decreased (P < 0.05) in WN toluene groups. A trend to increase in Na+/K+-ATPase was found in WN and MN toluene groups, while total ATPase increased (P < 0.05) in the WN 1.5 g toluene group. The results suggest that high concentrations of toluene in single doses induce significant changes in the serotonergic system and alter membrane fluidity more perceptibly in the brain of adult animals with regular diet than in malnourished animals.

Animals↗
PubMed1989

Effect of toluene on rat synaptosomal phospholipid methylation and membrane fluidity.

This study investigated the effects of toluene (1 g/kg, 1 hr, i.p.) on rat synaptosomal phospholipid methylation (PLM), phospholipid composition, and membrane fluidity. Toluene significantly decreased basal PLM (35%) in studies using [3H]methionine [( 3H]Met) as the methyl donor; this was reflected by similar decreases in phosphatidylmonomethylethanolamine (PME) (30%). No effects were observed in either PLM reactions that used [3H]adenosylmethionine [( 3H]AdoMet) as methyl donor, or AdoMet synthetase, suggesting that toluene preferentially affects PLM reactions that derive methyl groups from [3H]Met. Also, toluene decreased synaptosomal phosphatidylethanolamine (PE) (24%), the initial substrate for PLM, and the addition of PE back to PE-depleted synaptosomes restored methyltransferase activity. Agonist-stimulated PLM using norepinephrine (NE) demonstrated that agonist-receptor coupling returned PLM to control values in synaptosomes from toluene-treated rats. NE-stimulated PLM was also blocked by propranolol (PRO), suggesting a role for toluene in receptor-mediated events. Membrane fluidity studies demonstrated that in vivo administration of toluene increased the outer synaptosomal membrane fluidity, whereas in vitro administration of toluene had no effect. Our observations support a positive relationship between increased PLM activity and increased outer, not core, membrane fluidity. These data demonstrate that specific toluene-phospholipid interactions occur in synaptosomes, resulting in altered membrane composition, function and fluidity.

Animals↗
PubMed1984

The effects of ethanol on the kinetics of toluene in man.

Eleven men were exposed in an exposure chamber to toluene vapor (3.2 mmol/m3, 4.5 hr) with and without a simultaneous po intake of ethanol (15 mmol/kg body wt). The ethanol was administered 70 to 85 min after the onset of the toluene exposure to achieve maximum concentrations of toluene and ethanol in blood at the same time. During the exposure period the solvent concentrations in inspired and expired air as well as the pulmonary ventilation were determined. The solvent concentrations in blood were measured during and for 3 hr after the exposure period. No effect of ethanol on the pulmonary ventilation could be seen during the exposure period. Ethanol decreased the total uptake as well as the relative uptake of toluene. The maximum toluene concentration in the blood increased from 7.4 to 12.5 mumol/liter in the presence of ethanol and apparent clearance of toluene decreased significantly. Toluene exerted no effect on the uptake and elimination of ethanol in blood. The results indicate an influence of a moderate dose of ethanol on the kinetics of toluene. The distribution and/or elimination of toluene from the blood was inhibited resulting in increased tissue exposure.

Adult↗
PubMed1988

Effects of toluene treatment in vivo and in vitro on the binding characteristics of [3H]neurotensin in rat striatal membranes.

The effects of treatment with toluene in vivo (80 ppm, 3 days, 6 h/day) and in vitro (19 mumol/ml) were analyzed on the binding characteristics of [3H]neurotensin in rat striatal membranes. Exposure to toluene in vivo did not produce any significant effects on the binding characteristics of [3H]neurotensin. However, the addition of toluene in vitro caused a trend for a decreased Bmax value and produced a significantly reduced KD value of [3H]neurotensin binding. The absence of effects at 80 ppm indicates that the neurotensin receptor is relatively insensitive to toluene exposure, in contrast to, e.g. the dopamine agonist binding sites. Furthermore, the toluene response of the neurotensin receptor, as seen after treatment in vitro, is different from the responses seen in many monoamine receptors, which show decreased affinities following toluene exposure. It is possible that toluene is mediating its effects on the neurotensin receptor by changing the lipid micro-environment in which the receptor is situated. Another explanation would be that toluene selectively acts on the monoamine receptors, e.g. the more sensitive dopamine receptors, which through receptor-receptor interactions would cause the response seen in the neurotensin receptor. However, it cannot be excluded that the suggested receptor-receptor interaction itself is affected by toluene.

Administration, Inhalation↗
PubMed1991

The hearing loss associated with exposure to toluene is not caused by a metabolite.

Exposure to toluene causes a marked hearing loss in rats, and this effect has been observed in some human solvent abusers. The issue of whether toluene or one of its metabolites is responsible for this effect has not been examined. To attempt to resolve this issue, we manipulated the metabolism, and thus the circulating levels, of toluene as follows. Two groups of rats were exposed to phenobarbital (PB) in their drinking water (0.1%) for seven days to induce detoxifying liver enzymes; two other groups had access to PB-free water. Then half of the rats exposed to PB or water were exposed to filtered air or a concentration of toluene expected to cause hearing loss. Levels of toluene in blood were markedly reduced by the PB and the excretion of hippuric acid was increased. All rats were tested for auditory sensitivity by brainstem auditory-evoked response (BAER) audiometry using a 16-kHz tone pip. The rats exposed to toluene alone showed a marked reduction in the integrated BAER waveform, indicative of the expected hearing deficit. None of the other treated rats showed any deviation from controls (i.e., water and air). These results provide strong evidence that toluene itself is responsible for the auditory dysfunction. Toluene also caused the rats to increase their fluid consumption and urine output; these effects were not altered by PB. Identification of toluene as the proximal ototoxicant should facilitate the search for the mechanism of this effect.

Acoustic Stimulation↗
PubMed1990

Driving under the influence of toluene.

Toluene is the most common volatile used for sniffing among adolescents. During 1983-1987, 114 drivers were arrested in Norway with blood toluene concentrations (BTCs) greater than 10 microM. Only four of these drivers were women. The age range was 15-34 years, and the mean age was 21. The mean BTC was 109 microM. There was no simple relation between blood toluene concentration and degree of impairment, however, most drivers with BTCs greater than 100 microM were considered as impaired or probably impaired by toluene. In a five year prospective study of rearrests among drivers arrested for driving after toluene sniffing, 12 out of 15 drivers were rearrested. They were responsible for 40 cases of suspected driving under influence of toluene, alcohol, or other drugs. The blood levels of toluene determined in this study must be regarded as minimum concentrations, since the toluene concentration fell rapidly in samples stored at 4 degrees C or 23 degrees C. Blood samples from drivers suspected of driving under influence of toluene must therefore be kept frozen.

Administration, Inhalation↗
PubMed2004

Effects of the abused solvent toluene on recombinant P2X receptors expressed in HEK293 cells.

ATP acts as a neurotransmitter in both the peripheral and central nervous systems by activating receptors in the P2Y and P2X families. P2Y receptors are coupled to intracellular signaling pathways, while P2X receptors contain an integral membrane-spanning pore and act as ion channels. Previous studies have established that certain abused drugs such as alcohol inhibit P2X receptors. In this study, we have examined the sensitivity of both homomeric and heteromeric P2X receptors to toluene, a commercial solvent widely used as a drug of abuse. P2X receptors were transiently expressed in HEK293 cells, and agonist-gated currents were measured using whole-cell patch clamp electrophysiology. Toluene potentiated currents in cells expressing homomeric P2X2 or P2X4 subunits when ATP concentrations were near or below the EC50 concentration. This potentiation was rapid in onset, voltage independent and was readily reversed upon washout of the toluene-containing solution. The toluene-induced potentiation of P2X2 currents was not altered by lowering the pH of the recording media to 5.5 or by including the heavy-metal chelator EDTA in the recording solution. At maximal ATP concentrations, toluene did not affect ATP-gated currents in cells expressing P2X2 or P2X4 receptors. ATP-gated currents were also markedly potentiated by toluene in cells transfected with both P2X4 and P2X6 subunits. In contrast, P2X3 receptor currents were inhibited by toluene at both low and high ATP concentrations. HEK293 cells transfected with both P2X2 and P2X3 subunits showed non-desensitizing currents when stimulated with alpha, beta-methylene ATP. In these cells, toluene potentiated currents only at sub-maximal concentrations of alpha, beta-methylene ATP. The results of this study suggest that the abused solvent toluene affects the function of P2X receptors in a subunit-dependent and agonist-dependent fashion.

Adenosine Triphosphate↗