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

doi:10.1016/0300-483X(82)90098-1

Toxicology

Volume 23, Issues 2–3, 1982, Pages 197-212

https://doi.org/10.1016/0300-483X(82)90098-1 Get rights and content

Abstract

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 suggest the possibility of synergistic toxic responses.

References (35)

C.W. Louw et al.
Atmos. Environ.
(1977)
O.M. Bakke et al.
Toxicol. Appl. Pharmacol.
(1970)
G. Ungváry et al.
Toxicology
(1981)
K. Pyykkö
Biochim. Biophys. Acta
(1980)
K. Johannesen et al.
Biochim. Biophys. Acta
(1977)
O.H. Lowry et al.
J. Biol. Chem.
(1951)
T. Omura et al.
J. Biol. Chem.
(1964)
T. Matsubara et al.
Anal. Biochem.
(1976)
B.S.S. Masters et al.
The Preparation and properties of microsomal TPNH-cytochrome c reductase from pig liver
K. Einarsson et al.
J. Biol. Chem.
(1973)

G.M. Holder et al.

Arch. Biochem. Biophys.

(1975)

R.A. Prough et al.

Direct fluorimetric methods for measuring fixed-function oxidase action

U. Frommer et al.

FEBS Lett.

(1974)

S.S. Thorgeirsson et al.

Adv. Cancer Res.

(1977)

C.R. Wolf et al.

Chem.-Biol. Interact.

(1978)

J.M. Patel et al.

Biochem. Pharmacol.

(1979)

L. Perbellini et al.

Toxicol. Appl. Pharmacol.

(1980)

Cited by (76)

Single-chemical and mixture effects of multiple volatile organic compounds exposure on liver injury and risk of non-alcoholic fatty liver disease in a representative general adult population
2023, Chemosphere
Evidence on liver injury and non-alcoholic fatty liver disease (NAFLD) from volatile organic compounds (VOCs) exposure is insufficient. A cross-sectional study including 3011 US adults from the National Health and Nutrition Examination Survey was conducted to explore the associations of urinary exposure biomarkers (EBs) for 13 VOCs (toluene, xylene, ethylbenzene, styrene, acrylamide, N,N-dimethylformamide, acrolein, crotonaldehyde, 1,3-butadiene, acrylonitrile, cyanide, propylene oxide, and 1-bromopropane) with liver injury biomarkers and the risk of NAFLD by performing single-chemical (survey weight regression) and mixture (Bayesian kernel machine regression [BKMR] and weighted quantile sum [WQS]) analyses. We found significant positive associations of EBs for toluene and 1-bromopropane with alanine aminotransferase (ALT), EBs for toluene, crotonaldehyde, and 1,3-butadiene with asparate aminotransferase (AST), EBs for 1,3-butadiene and cyanide with alkaline phosphatase (ALP), EBs for xylene and cyanide with hepamet fibrosis score (HFS), EBs for the total 13 VOCs (except propylene oxide) with United States fatty liver index (USFLI), and EBs for xylene, N,N-dimethylformamide, acrolein, crotonaldehyde, and acrylonitrile with NALFD; and significant inverse associations of EBs for ethylbenzene, styrene, acrylamide, acrolein, crotonaldehyde, 1,3-butadiene, acrylonitrile, cyanide, and propylene oxide with total bilirubin, EBs for ethylbenzene, styrene, acrylamide, acrolein, 1,3-butadiene, acrylonitrile, and cyanide with albumin (ALB), EBs for ethylbenzene, styrene, acrylamide, N,N-dimethylformamide, acrolein, crotonaldehyde, 1,3-butadiene, acrylonitrile, cyanide, and propylene oxide with total protein (TP), and EB for 1-bromopropane with AST/ALT (all P-FDR<0.05). In BKMR and WQS, the mixture of VOC-EBs was significantly positively associated with ALT, AST, ALP, HFS, USFLI, and the risk of NAFLD, while significantly inversely associated with TBIL, ALB, TP, and AST/ALT. VOCs exposure was associated with liver injury and increased risk of NAFLD in US adults. These findings highlight that great attention should be paid to the potential risk of liver health damage from VOCs exposure.
Ecological risk assessment for xylenes and propylbenzenes in aquatic environment using a species sensitivity distribution approach
2023, Ecotoxicology and Environmental Safety
Xylenes and propylbenzenes (PBZs) are volatile aromatic hydrocarbons with high aquatic toxicity. Xylenes can be present in three isomers: o-xylene (OX), m-xylene (MX), and p-xylene (PX), while PBZs include two isomers: n-propylbenzene (n-PBZ) and isopropylbenzene (i-PBZ). Their accidental spills and improper discharges from petrochemical industries can cause severe contamination in water bodies posing potential ecological risks. In this study, the published acute toxicity data of these chemicals for aquatic species were collected to calculate hazardous concentrations protecting 95% species (HC₅) using a species sensitivity distribution (SSD) approach. The acute HC₅ values for OX, MX, PX, n-PBZ, and i-PBZ were estimated to be 1.73, 3.05, 1.23, 1.22, and 1.46 mg/L, respectively. The risk quotient (RQ) values calculated based on HC₅ indicated their high risk (RQ: 1.23 ∼ 21.89) in groundwater, but low risk (RQ < 0.1) in natural seawater, river water, and lake water. When xylenes or PBZs leaked into the sea, they were expected to pose a high risk (RQ > 1) at the start and then a low risk (RQ < 0.1) after 10 days due to natural attenuation. These results may help to derive more reliable protection thresholds for xylenes and PBZs in aquatic environment and provide a basis for evaluating their ecological risks.
RIFM fragrance ingredient safety assessment, xylene (mixed), CAS Registry Number 1330-20-7
2021, Food and Chemical Toxicology
Citation Excerpt :
Chapter 9, Animal Models, in section: “Comparative Physiology and Anatomy,” subsection, “Comparative Airway Anatomy.” Additional References: Smyth (1962); Frantik (1994); Carpenter (1975); Hass (1995); Klimisch (1988); Stadler (1996); Kulig (1997); Hass (1993); Jenkins (1970); Kawai (1991); Savolainen (1979); Savolainen (1985); Toftgard (1981); Toftgard (1982); Laine (1993); Smith (1997); Tatrai (1980); Wallace (1987); Prah (1998); DeJongh (1998); Loizou (1999); Kukner (1998); Saillenfait (2003); Vaidyanathan (2003); Gagnaire (2007); Ernstgard (2002); Sandikci (2009); Gauthereau-Torres (2009); Martin (2012); Wang (2012); Alexeeff (2006). Literature Search and Risk Assessment Completed On: 05/09/19.
Effects of inhaled combined Benzene, Toluene, Ethylbenzene, and Xylenes (BTEX): Toward an environmental exposure model
2021, Environmental Toxicology and Pharmacology
Citation Excerpt :
In addition, because the reported exposures were below OSHA limits, these results may be relevant to environmental exposures. Animal studies have also demonstrated kidney and/or liver damage after exposure to benzene (10−50 ppm for 5 h/day, for 2 weeks; El-Shakour et al., 2015), toluene (2000 ppm of various durations; Pyykko, 1983), ethylbenzene (100−1500 ppm for 6 h/day, for 13 weeks; Zhang et al., 2010), and xylenes (2000 ppm for 6 h/day for 3 days; Toftgard and Nilsen, 1982). Because the kidney and liver are also susceptible to the toxic effects of BTEX tested at various concentrations for various durations, the lack of an animal model of combined BTEX exposure is a significant gap in BTEX research.
Combined environmental exposures to the volatile organic compounds (VOCs) Benzene, Toluene, Ethylbenzene, and Xylene (BTEX) pose clear risks to public health. Research into these risks is under-studied even as BTEX levels in the atmosphere are predicted to rise. This review focuses on the available literature using single- and combined-BTEX component inhaled solvent exposures in animal models, necessarily also drawing on findings from models of inhalant abuse and occupational exposures. Health effects of these exposures are discussed for multiple organ systems, but with particular attention on neurobehavioral outcomes such as locomotor activity, impulsivity, learning, and psychopharmacological responses. It is clear that animal models have significant differences in the concentrations, durations and patterns of exposure. Experimental evidence of the deleterious health and neurobehavioral consequences of exposures to the individual components of BTEX were found, but these effects were typically assessed using concentrations and exposure patterns not characteristic of environmental exposure. Future studies with animal models designed appropriately to explore combined BTEX will be necessary and advantageous to discovering health outcomes and more subtle neurobehavioral impacts of long-term environmental exposures.
The genotoxicity of an organic solvent mixture: A human biomonitoring study and translation of a real-scenario exposure to in vitro
2020, Regulatory Toxicology and Pharmacology
Citation Excerpt :
Thus, it can be concluded that, when there is a substance that competes with another for the same metabolic pathway, one should check whether they are enzyme-inducing or inhibiting, since if one of the substances is inhibitory the other substance is expected to increase in the blood (Viau, 2002). Concerning xylene and its isomers, one study revealed that they can increase hepatic CYP450 concentrations and have the ability to proceed to metabolic modifications of other potentially toxic substances in liver, kidney and lung microsomes, suggesting possible synergistic toxic responses (Toftgård and Nilsen, 1982). In the comet assay performed in this study, an additional step was added to make the assay more specific and sensitive, allowing the evaluation of oxidative damage through the use of the Fpg enzyme.
This study aimed to evaluate occupational exposure to a styrene and xylene mixture through environmental exposure assessment and identify the potential genotoxic effects through biological monitoring. Secondly, we also exposed human peripheral blood cells in vitro to both xylene and styrene either alone or in mixture at concentrations found in occupational settings in order to understand their mechanism of action. The results obtained by air monitoring were below the occupational exposure limits for both substances. All biomarkers of effect, except for nucleoplasmic bridges, had higher mean values in workers (N = 17) compared to the corresponding controls (N = 17). There were statistically significant associations between exposed individuals and the presence of nuclear buds and oxidative damage. As for in vitro results, there was no significant influence on primary DNA damage in blood cells as evaluated by the comet assay. On the contrary, we did observe a significant increase of micronuclei and nuclear buds, but not nucleoplasmic bridges upon in vitro exposure. Taken together, both styrene and xylene have the potential to induce genomic instability either alone or in combination, showing higher effects when combined. The obtained data suggested that thresholds for individual chemicals might be insufficient for ensuring the protection of human health.
The role of toxicokinetics in xylene-induced ototoxicity in the rat and guinea pig
2007, Toxicology
In the rat, some aromatic solvents cause a high level of ototoxicity that is characterized by damage to outer hair cells in the cochlea, which results in irreversible hearing loss. However, there is a vast difference in their potency. Among the three isomers of xylene, only para-xylene has been shown to be ototoxic in the rat. Moreover, all the species do not show the same susceptibility to ototoxic solvents, the rat being the most susceptible and the guinea pig seeming resistant to this ototoxic effect. The objective of the study was to determine whether toxicokinetic factors could explain the differences in ototoxicity observed among the three isomers of xylene in the rat and the species-dependent ototoxicity in the rat and the guinea pig. Blood and brain concentrations of each isomer were monitored in Sprague–Dawley rats treated orally by gastric intubation with a single dose or a 10 day-repeated treatment of 8.47 mmol/kg (an ototoxic dosage for para-xylene) of each isomer. Moreover, histology of the cochlea was carried out and the toxicokinetics of meta-xylene was monitored in rats treated with a single dose or a 10 day-repeated treatment of 16.94 mmol/kg meta-xylene, a non-ototoxic isomer. Similarly, histology of the cochlea was carried out and the toxicokinetics of para-xylene was followed in guinea pigs treated by gavage with a single dose or a 10 day-repeated treatment of 8.47 mmol/kg para-xylene. Finaly, the blood and brain concentrations of para-xylene were measured in both the rats and the guinea pigs after a 4-h exposure to 1800 ppm of para-xylene. Among the three isomers studied, para-xylene yielded the highest blood and brain concentrations in the acutely and repeatedly exposed rats. When given a high dosage of meta-xylene (16.94 mmol/kg), the rats showed blood and brain concentrations of meta-xylene in the same order as those obtained with 8.47 mmol/kg para-xylene, but no outer hair cell loss was observed. No outer hair cell loss was observed in the guinea pigs treated with para-xylene. Whatever the exposure pattern, the blood and brain concentrations of para-xylene in the rats were 3.1–9.5 times higher than those measured in the guinea pigs. These results indicate that toxicokinetic factors cannot explain the differences in ototoxicity observed with the three isomers in the rat. However, they suggest that the differences in susceptibility to para-xylene observed between the rats and the guinea pigs might be due to toxicokinetic factors.

View all citing articles on Scopus

View full text

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

Abstract

Atmos. Environ.

Toxicol. Appl. Pharmacol.

Toxicology

Biochim. Biophys. Acta

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Anal. Biochem.

J. Biol. Chem.

Arch. Biochem. Biophys.

FEBS Lett.

Adv. Cancer Res.

Chem.-Biol. Interact.

Biochem. Pharmacol.

Toxicol. Appl. Pharmacol.