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At least 19 recordsLinked to original sources
PubMed1989

Metabolism of antipyrine and m-xylene in rats after prolonged pretreatment with xylene alone or xylene with ethanol, phenobarbital or 3-methylcholanthrene.

1. The metabolic disposition of antipyrine (AP) and m-xylene (XYL) has been studied in rats pretreated for a prolonged period with XYL, dosed alone or in combination with ethanol, phenobarbital (PB), or 3-methylcholanthrene (MC). 2. XYL inhalation exposure at 300 ppm in air (7 h/day, 4 days/week, for 1 or 4 weeks) did not alter the total 24-h recovery of AP and its major metabolites in urine, but the excretion profile changed compared with controls: 3-hydroxymethylantipyrine (3-HMA) increased (less than or equal to 14%, P less than 0.001), norantipyrine (NORA) (less than or equal to 23%, P less than 0.01) and AP (less than or equal to 53%, P less than 0.01) decreased. 4-Hydroxyantipyrine (4-OHA) was unchanged. 3. Oral dosage of XYL at 800 mg/kg per day (5 days/week, for 12 days) altered the metabolic disposition of AP similarly to inhalation. 4. XYL + ethanol did not alter the xylene-type effect on AP metabolism. This was at variance with the changes following XYL + PB and, to a greater extent, XYL + MC pretreatments: 4-OHA increased (53-74%, P less than 0.01), 3-HMA (11-42%, P less than 0.05) and AP (greater than or equal to 50%, P less than 0.05) decreased. The effect on NORA was less clear. 5. XYL pretreatment accelerated metabolic disposition of its major urinary metabolite, methylhippuric acid (MHA) and formation of thioethers. 6. Thioether excretion in 24 h urine was enhanced about 10-fold after XYL inhalation and 20-fold after oral administration. Only XYL + PB treatment enhanced further the excretion of xylene-derived thioethers (P less than 0.05). 7. Drug-metabolizing activity (phase I and II reactions) in liver, lung and kidney showed that the treatments resulted in marked and differential biochemical alterations. 8. In conclusion, m-xylene enhanced the rate of its own metabolism and induced differential changes on urinary AP metabolite profile depending on the pretreatment.

Administration, Inhalation↗
PubMed1999

Possible preferential metabolism of xylene isomers following occupational exposure to mixed xylenes.

OBJECTIVES: Solvent exposures commonly involve mixtures of substances or mixtures of isomers of a single solvent. These may be metabolised through common pathways, resulting in the potential for metabolic interactions. These may then lead to accumulation of solvent or metabolic intermediates, some of which may be toxic. This paper describes a pilot study conducted to determine the correlation between airborne xylene isomers and the appearance of methylhippuric acid (MHA) isomers in urine of workers exposed mainly to xylene. The project also aimed to determine whether there is preferential metabolism of any isomer by comparison of the ratios of airborne isomers with the ratios of metabolite isomers appearing in urine. SUBJECTS AND METHODS: A total of 12 workers (11 male, 1 female) were recruited into this study, with 2 of the participants providing samples on more than one occasion. Workers included flooring contractors (5), printers (2), chemical manufacturers (2), histology technicians (2) and one householder using a xylene-based varnish. Subjects were aged between 24 and 48 years (37.6+/-2.0 years; mean +/- SEM). After giving informed consent, workers provided a prework and postwork urine sample on a midweek work day. Samples were stored frozen prior to analysis. Breathing-zone air samples were collected using personal air samplers at 50 ml/min. Solvents were trapped on activated-charcoal sampling tubes. Subjects wore pumps for 18-304 (178+/-24) min on the same day on which urine samples were collected. RESULTS: Xylene exposures ranged from 1.6 to over 7000 ppm. In all, 7 of 16 measurements exceeded the Australian TWA standard of 80 ppm. Two of the flooring contractors wore respiratory protective equipment (RPE) and the two histopathology technicians used workplace ventilation systems. Total urinary MHA output ranged from 10 to 8000 mmol/mol creatinine, with 6 of 16 samples exceeding the modified biological exposure index of 702 mmol/mol. Correlations between airborne concentrations of individual xylene isomers and their corresponding MHA isomers were poor but improved when workers using RPE were excluded from the analysis. Gradients of the regression lines (millimoles of MHA per mole of creatinine per parts per million of xylene) were 3.2 for o-isomers, 7.0 for p-isomers, and 14.4 for m-isomers. Comparisons of isomer ratios of xylene in air were made with the corresponding ratio of MHA isomers in urine. These revealed higher ratios of m-MHA to other MHA isomers than those of m-xylene to the other xylene isomers. The MHA isomer ratios were expected to be the same as the airborne xylene isomer ratios if there were no preferential elimination of any isomer. m-MHA appeared in urine in a greater proportion than would be predicted from the proportion of m-xylene detected in air. The time course of the appearance of MHA isomers in urine also suggests that interactions were taking place, with m-MHA appearing in high proportion in urine following several days of repeated heavy xylene exposure. On a single moderate exposure, m-MHA appeared initially in high proportion in the first few hours but was undetectable in urine after 18 h. p-MHA was detectable for up to 6 h after exposure, and o-MHA remained detectable after 18 h. CONCLUSIONS: This study suggests that excretion of m-MHA in urine is favoured over that of the other isomers following exposure to mixed xylenes. This is independent of airborne xylene isomer composition and suggests that the metabolism of m-xylene occurs preferentially to that of the other isomers. It is not clear at which step in the metabolism of xylene this preference occurs, although other work indicates that the initial oxidation of xylene to methylbenzyl alcohol by cytochrome P450 2E1 occurs at the same rate for each isomer. These findings suggest that there is potential for metabolic interactions between xylene isomers and that these may be the basis for xylene toxicity.

Adult↗
PubMed1982

Effects of xylene and xylene isomers on cytochrome P-450 and in vitro enzymatic activities in rat liver, kidney and lung.

Rats were exposed for 3 days by inhalation to 2000 ppm of a xylene mixture, or the individual constituents, o-xylene, m-xylene, p-xylene and ethylbenzene. All solvents increased hepatic cytochrome P-450 concentrations and NADPH-cytochrome c reductase activity, although p-xylene did not increase the cytochrome P-450 content as much as the other compounds, showing the importance of the substitution pattern. Increases were observed in the in vitro O-deethylation of 7-ethoxyresorufin and in the hydroxylation of n-hexane and benzo[a]pyrene. The metabolite profiles obtained with these substrates and the results of gel electrophoresis in the presence of sodium dodecyl sulfate indicate that the induction is of the phenobarbital type. In kidney microsomes an increased concentration of cytochrome P-450 was obtained following exposure to a xylene mixture or to o- or m-xylene. The O-deethylation of 7-ethoxyresorufin was increased by exposure to all solvents. In lung microsomes xylene and xylene isomers but not ethylbenzene caused a decrease in cytochrome P-450 content and a reduction in n-hexane hydroxylation. However, the O-deethylation of 7-ethoxyresorufin was not affected. In general the effect of the xylene mixture reflected the content of the dominating component m-xylene. The ability of xylene and xylene isomers to modify the metabolism of other potentially toxic substances in liver, kidney and lung microsomes suggests the possibility of synergistic toxic responses.

Animals↗
PubMed1993

Excretion of methylhippuric acids in urine of workers exposed to a xylene mixture: comparison among three xylene isomers and toluene.

The correlation between exposure to three xylene isomers and resulting urinary excretion of corresponding methylhippuric acid (MHA) isomers was studied among 175 Chinese workers of both sexes who had been predominantly exposed to xylenes (exposure to xylenes accounting for 70% or more of the total exposure on a ppm basis). Nonexposed controls (281 men and women) were also studied to define the background level of MHAs in urine. The solvent exposure of xylene-exposed workers during their workshift was monitored by diffusive sampling of breathing zone air, and MHAs in shift-end urine were determined by high-performance liquid chromatography. Regression analysis showed that the concentration of each MHA isomer correlated significantly with the time-weighted average intensity of exposure to the corresponding xylene isomer, and therefore the correlation between the sum of three xylene isomers in air and that of three MHA isomers in urine was also significant; the slope of the regression line was essentially the same among the three isomers. The calculated regression line suggested that the urinary MHA level after hypothetical exposure to xylenes at 100 ppm will be somewhat less than the proposed biological exposure index and biological tolerance value. Two social habits of smoking and drinking in combination suppressed the conversion of xylenes to MHAs in male workers.

Adult↗
PubMed1991

Degradation of toluene and m-xylene and transformation of o-xylene by denitrifying enrichment cultures.

Seven different sources of inocula that included sediments, contaminated soils, groundwater, process effluent, and sludge were used to establish enrichment cultures of denitrifying bacteria on benzene, toluene, and xylenes in the absence of molecular oxygen. All of the enrichment cultures demonstrated complete depletion of toluene and partial depletion of o-xylene within 3 months of incubation. The depletion of o-xylene was correlated to and dependent on the metabolism of toluene. No losses of benzene, p-xylene, or m-xylene were observed in these initial enrichment cultures. However, m-xylene was degraded by a subculture that was incubated on m-xylene alone. Complete carbon, nitrogen, and electron balances were determined for the degradation of toluene and m-xylene. These balances showed that these compounds were mineralized with greater than 50% conversion to CO2 and significant assimilation into biomass. Additionally, the oxidation of these compounds was shown to be dependent on nitrate reduction and denitrification. These microbial degradative capabilities appear to be widespread, since the widely varied inoculum sources all yielded similar results.

Bacteria, Anaerobic↗
PubMed1989

The effect of m-xylene on rat lung benzo[a]pyrene metabolism and microsomal membrane lipids: comparison with p-xylene.

m-Xylene (1 g/kg, i.p., 1 h) was shown to decrease aryl hydrocarbon hydroxylase (AHH) activity, a detoxification pathway for benzo[a]pyrene (BaP), in the rat lung. Inhibition was maximal at 1 g/kg, 1 h after treatment and was sustained for at least 24 h. Reduction in cytochrome P-450 activity in rat lung was also observed, while liver activity was unchanged. p-Xylene has been previously shown to produce a similar pattern of MFO changes in rat lung. The lipid composition of the microsomal membrane is important to mixed function oxidase (MFO) regulation and function. Since the xylenes are lipophilic, these compounds were studied to determine whether they alter pulmonary microsomal lipids. p-Xylene produced an organ specific increase in lipid peroxidation in the rat lung. This was accompanied by decreases in lung microsomal total phospholipid (PL) and phosphatidylcholine (PC) content. Pulmonary microsomal membrane fluidity was also reduced by p-xylene administration. In comparison, m-xylene administration did not change any of the lipid membrane parameters tested. These divergent results leave unresolved the role of altered PL metabolism in solvent-induced inhibition of MFO activity.

Animals↗
PubMed1999

Anaerobic oxidation of o-xylene, m-xylene, and homologous alkylbenzenes by new types of sulfate-reducing bacteria.

Various alkylbenzenes were depleted during growth of an anaerobic, sulfate-reducing enrichment culture with crude oil as the only source of organic substrates. From this culture, two new types of mesophilic, rod-shaped sulfate-reducing bacteria, strains oXyS1 and mXyS1, were isolated with o-xylene and m-xylene, respectively, as organic substrates. Sequence analyses of 16S rRNA genes revealed that the isolates affiliated with known completely oxidizing sulfate-reducing bacteria of the delta subclass of the class Proteobacteria. Strain oXyS1 showed the highest similarities to Desulfobacterium cetonicum and Desulfosarcina variabilis (similarity values, 98.4 and 98.7%, respectively). Strain mXyS1 was less closely related to known species, the closest relative being Desulfococcus multivorans (similarity value, 86.9%). Complete mineralization of o-xylene and m-xylene was demonstrated in quantitative growth experiments. Strain oXyS1 was able to utilize toluene, o-ethyltoluene, benzoate, and o-methylbenzoate in addition to o-xylene. Strain mXyS1 oxidized toluene, m-ethyltoluene, m-isoproyltoluene, benzoate, and m-methylbenzoate in addition to m-xylene. Strain oXyS1 did not utilize m-alkyltoluenes, whereas strain mXyS1 did not utilize o-alkyltoluenes. Like the enrichment culture, both isolates grew anaerobically on crude oil with concomitant reduction of sulfate to sulfide.

Alkylation↗
PubMed1991

The toxic effects of combined exposure to toluene and m-xylene in animals. II. Blood toluene and m-xylene during single and combined exposure in rats.

The influence of combined exposure to m-xylene and toluene vapours at a concentration of 100 + 100 ppm on blood m-xylene concentration in rats was investigated. Within 6-7 hours of coexposure to m-xylene and toluene a significant increase in blood m-xylene concentration, in comparison to single exposure to m-xylene at concentration of 100 ppm, was observed. Study results may suggest that, reported earlier, the more than additive toxic effects of combined exposure to m-xylene and toluene in animals may result from its metabolic interaction.

Animals↗
PubMed1986

The developmental toxicity of xylene and xylene isomers in the Hydra assay.

Two laboratories tested multiple forms of xylene for their developmental toxicity hazard potential (A/D ratio) by means of the hydra assay. The three isomers, as well as a solution of mixed xylenes, all interfered with development (D) at or near to concentrations that also were toxic to adult (A) hydra. The A/D ratios ranged from 1 to 2 in hydra as they had in conventional tests made in pregnant laboratory animals. Each testing laboratory concluded that xylenes were not primary developmental hazards but coaffective agents capable of disrupting development only at or near to concentrations also toxic to adults. In each instance every xylene tested interfered with the same stage or developmental sequence and in a concentration-related manner. The hydra assay may be useful for establishing priorities to test agents in a more elaborate system, but substances less soluble than xylene may exceed the test's applicability.

Animals↗
PubMed1983

[Regulation of the enzyme activity of para-xylene catabolism in a spontaneous para-xylene-negative variant of Pseudomonas aeruginosa 2x79].

A spontaneous variant of Pseudomonas aeruginosa 2x unable to grow on p-xylene as the sole source of carbon and energy has been isolated. p-Xylenenegative variant of P. aeruginosa 2x79 differs from the wild type strain by the character of growth on the p-xylene oxidation intermediates p-toluate and protocatochuate. The cell of 2x79 variant inability to grow on p-xylene has been shown to be accompanied by the elimination of the activities of three enzymes - p-xylene methylhydroxylase, p-cresol methylhydroxylase and metapyrocatechase and by the considerable alteration in the regulation of orto-cleavage aromatic ring enzymes activity pyrocatechase and protocatechuate-3,4-dioxygenase. Possible reasons for appearing spontaneous variants 2x79 in the population of P. aeruginosa 2x growing on the p-xylene are being discussed.

Benzoates↗
PubMed1988

Oral toxicology studies with xylene isomers and mixed xylenes.

Xylene isomers and mixed xylenes were administered to male and female Sprague-Dawley rats to evaluate their effects on standard toxicological parameters which included body and organ weights, hematology, serum chemistries, urinalysis and histopathological examination. In the initial study, m, o- or p-xylene were administered in corn oil by gavage for 10 consecutive days at dose levels of 250, 1000 and 2000 mg/kg/day. The most noteworthy changes were increased liver weight in both sexes for all three isomers while decreases in spleen and thymus weights were seen less frequently. Rats were subsequently exposed to mixed xylenes by gavage in corn oil for 90 consecutive days at dose levels of 150, 750 and 1500 mg/kg/day. The most significant findings of the subchronic study were enlarged livers and kidneys. Histopathological evaluation of liver and kidney tissues revealed an increased incidence of minimal chronic renal disease in only female rats, while treatment related hepatic histopathological changes were not detected in either sex.

Administration, Oral↗
PubMed1996

The effect of ageing and in vitro exposure to xylene and KCl on [Ca2+]i in synaptosomes from rats exposed prenatally to xylene.

Female rats (Mol: WIST) were exposed prenatally to 500 p.p.m. of technical xylene on days 7-20. At the age of fourteen months the rats were sacrificed and the synaptosomal fraction prepared for in vitro studies. The cytosolic calcium concentration was measured using the FURA-2 technique. The cytosolic calcium was increased in synaptosomes from old rats compared to those from rats at the age of three months, but no effect of prenatal exposure was seen. When synaptosomes were incubated with xylene, potassium or both, the cytosolic calcium concentration was changed identically in all groups of rats. When synaptosomes were incubated simultaneously to xylene and potassium a dramatical leakage of FURA-2 was observed. The mechanisms behind the membrane leakage are discussed.

Aging↗
PubMed1997

Induction of mouse cytochrome P450 2B enzymes by amine metabolites of musk xylene: contribution of microsomal enzyme induction to the hepatocarcinogenicity of musk xylene.

Musk xylene (MX) is a synthetic nitromusk perfume ingredient that, although uniformly negative in genotoxicity testing, causes liver tumors in B6C3F1 mice. MX is also capable of inducing cytochrome P450 enzymes in a manner similar to that of phenobarbital (PB), which suggests that epigenetic mechanisms may be involved in the carcinogenic response. At the same time, MX is metabolized in vivo by nitroreduction, a reaction catalyzed by intestinal flora that yields aromatic amine metabolites. These amine metabolites are also capable of inactivating CYP2B10, the major cytochrome P450 enzyme induced by MX treatment. In the study reported here, the monoamine metabolites of MX, o- and p-NH2-MX, were evaluated for their potential to induce CYP2B10 and CYP1A2 mRNAs. Northern blot analyses indicated that both amines markedly induced CYP2B10 mRNA, whereas CYP1A2 mRNA, the enzyme implicated in the bioactivation of aromatic amines and frequently induced by aromatic amines, was induced only slightly, a response that was not different from that seen with PB. Induction of CYP2B10 mRNA suggested that the amine metabolites may contribute to the enzyme induction profile seen with MX treatment. To test this hypothesis, mice were treated with broad-spectrum antibiotics (neomycin, tetracycline, and bacitracin) to eliminate the intestinal flora and prevent formation of o- and p-NH2-MX. In antibiotic-treated mice treated with MX (200 mg/kg) for 4 d, no evidence of microsomal enzyme induction was observed, including no increases in liver weight, total cytochrome P450 content, or CYP2B protein levels. These results indicate that the amine metabolites of MX are responsible for the enzyme induction seen after MX administration. Thus, the biochemical and molecular effects of amine metabolites of MX are markedly different from those of other aromatic amines but very similar to those of PB. Therefore, it appears that MX is a non-genotoxic chemical that may cause mouse liver tumors in a manner analogous to that of PB.

Amines↗