Abstract
Rats were exposed to 0, 75, 150 or 300 ppm (1 ppm=1 cm3/m3=4.35 mg/m3) m-xylene for 24 h and then killed. In the lungs, the cytochrome P-450 decreased to 45, 13 and 20% of the control value with the increasing exposure intensity and the activity of 7-ethoxycoumarin O-deethylase to 70, 27 and 14%, respectively. The activity of epoxide hydrolase increased slightly after exposures both at 150 (1.6-fold) and 300 cm3/m3 (1.4-fold), while the other measured drug-metabolizing enzyme activities showed no consistent changes. The non-protein sulfhydryl group content of the lungs was not affected. The concentrations of m-xylene in blood indicated that the solvent uptake increased in the different exposure groups more than expected, based on atmospheric concentrations alone. Morphologic studies of the lungs with scanning electron microscopy showed no apparent changes after exposure to 300 cm3/m3 or after a high oral dose (2 ml/kg/day, 3 days).
Inhalation exposure to m-xylene for 5 weeks (7 h/day, 4 days/week) at a concentration of 300 ppm lowered the contents of cytochrome P-450 in rat lungs to 65% and the activity of 7-ethoxycoumarin O-deethylase to 41% without any other marked effects on the other drug-metabolizing enzymes or on the levels of non-protein sulfhydryl groups.
In this study, the selective destruction of cytochrome P-450 in rat lung could be shown both after acute and subacute exposures and at concentrations low enough to warrant occupational concern.
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References
Aitio A (1978) A simple and sensitive assay of 7-ethoxycoumarin deethylation. Anal Biochem 85: 488–491
Åstrand I (1975) Uptake of solvents in the blood and tissues of man. A review. Scand J Work Environ Health 1: 199–218
Ayesh R, Idle JR, Ritchie JC, Crothers MJ, Hetzel MR (1984) Metabolic oxidation phenotypes as markers for susceptibility to lung cancer. Nature 312: 169–170
Boyd MR (1977) Evidence for the Clara cell as a site of cytochrome P-450-dependent mixed-function oxidase activity in lung. Nature 269: 713–715
Boyd MR (1980) Biochemical mechanisms in chemical-induced lung injury: Roles of metabolic activation. CRC Crit Rev Toxicol 7: 103–176
Boyd MR, Statham CN, Longo NS (1980) The pulmonary Clara cell as a target for toxic chemicals requiring metabolic activation: Studies with carbon tetrachloride. J Pharmacol Exp Ther 212: 109–214
Boyd MR, Grygiel JJ, Minchin RF (1983) Metabolic activation as a basis for organ-selective toxicity. Clin Exp Pharmacol Physiol 10: 87–99
Bradbury SL, Clark FJ, Steinman CR, Jakoby WB (1975) Aldehyde dehydrogenase from Baker's yeast. Methods Enzymol 41: 354–360
Dean BJ (1978) Genetic toxicology of benzene, toluene, xylenes and phenols. Mutat Res 47: 75–97
Devereux TR, Serabjit-Singh CJ, Slaughter SR, Wolf CR, Philpot RM, Fouts JR (1981) Identification of pulmonary cytochrome P-450 isoenzymes in nonciliated bronchiolar epithelial (Clara) and alveolar type II cells isolated from rabbit lung. Exp Lung Res 2: 221–230
Engström K, Riihimäki V (1987) Determination of xylene in blood. In: Fishbein L, O'Neill IK (eds) Environmental carcinogens. Selected methods of analyses. Vol 10 — Benzene, toluene and xylene. IARC Scientific Publications (in press)
Fiserova-Bergerova V (1985) Toxicokinetics of organic solvents. Scand J Work Environ Health 11, suppl 1: 7–21
Giuliano KA, Lau EP, Fall RR (1980) Simplified liqouid chromatographic assay for epoxide hydrolase. J Chromatogr 202: 447–452
Habig WH, Babst MJ, Jakoby WB (1974) Glutathione. S-transferases: The first enzymatic step in mercapturic acid formation. J Biol Chem 249: 7130–7139
Johannesen KAM, DePierre JW (1978) Measurement of cytochrome P-450 in the presence of large amounts of contaminating hemoglobin and methemoglobin. Anal Biochem 86: 725–732
Lowry OH, Rosenbrough HJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193: 265–275
Malick LE, Wilson RB (1975) Modified thiocarbohydrazide procedure for scanning electron microscopy: Routine use for normal, pathological, or experimental tissues. Stain Technol 50: 265–269
Minchin RF, Boyd MR (1983) Localization of metabolic activation and deactivation systems in the lung: Significance to the pulmonary toxicity of xenobiotics. Ann Rev Pharmacol Toxicol 23: 217–238
NIOSH (National Institute for Occupational Safety and Health) (1975) Criteria for a recommended standard. Occupational exposure to xylene, US. Department of Health Education and Welfare. Washington DC: US Government Printing Office
Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 239: 2370–2378
Patel JM (1979) The destruction of pulmonary and hepatic cytochrome P-450 by phthaldehyde. Toxicol Appl Pharmacol 48: 337–342
Patel JM, Harper C, Drew RT (1978) The biotransformation of pxylene to a toxic aldehyde. Drug Metab Dispos 6: 368–374
Patel JM, Wolf CR, Philpot RM (1979) Interaction of 4-methyl-benzaldehyde with rabbit pulmonary cytochrome P-450 in the intact animal microsomes and purified systems. Biochem Pharmacol 28: 2031–2036
Phillips A, Langdon RG (1962) Hepatic diphosphopyridine nucleotide cytochrome c reductase: Isolation, characterization and kinetic studies. J Biol Chem 237: 2652–2660
Philpot RM, Wolf CR (1981) The properties and distribution of the enzymes of pulmonary cytochrome P-450-dependent monooxygenase systems. In: Hodgson E, Bend JR, Philpot RM (eds) Rev Biochem Toxicology vol 3: 51–76, Elsevier, Amsterdam
Philpot RM, Smith BR (1984) Role of cytochrome P-450 and related enzymes in the pulmonary metabolism of xenobiotics. Environ Health Persp 55: 359–367
Pyykkö K (1980) Effects of methylbenzenes on microsomal enzymes in rat liver, kidney and lung. Biochem Biophys Acta 633: 1–9
Pyykkö K (1983) Characterization and stability of rat liver microsomes isolated by rapid gel filtration method. Acta Pharmacol Toxicol 52: 39–46
Pyykkö K, Paavilainen S, Metsä-Ketelä T, Laustiola K (1987) The increasing and decreasing effects of aromatic hydrocarbon solvents on pulmonary and hepatic cytochrome P-450 in rat. Acta Pharmacol Toxicol 60: 288–293
Ramsey JC, Young JD (1978) Pharmacokinetics of inhaled styrene in rats and humans. Scand J Work Environ Health 4, suppl 2: 84–91
Riihimäki V, Pfäffli P, Savolainen K, Pekari K (1979) Kinetics of m-xylene in man: General features of absorption, distribution, biotransformation and excretion in repetitite inhalation exposure. Scand J Work Environ Health 5: 217–231
Saville B (1958) A scheme for the colorimetric determination of microgram amounts of thiols. Analyst 83: 670–672
Serabjit-Singh CJ, Wolf CR, Philpot RM, Plopper CG (1980) Cytochrome P-450: Localization in rabbit lung. Science 207: 1469–1470
Smith BR, Bend JR (1981) Metabolic interaction of hydrocarbons with mammalian lung. In: Hodgson E, Bend JR, Philpot RM (eds) Reviews in biochemical toxicology. Elsevier North Holland, Inc., Amsterdam, vol 3: pp 77–122
Smith BR, Plummer JL, Wolf CR, Philpot RM, Bend JR (1982) p-Xylene metabolism by rabbit lung and liver and its relationship to the selective destruction of pulmunary cytochrome P-450. J Pharmacol Exp Ther 223: 736–742
Toftgård R, Nilsen OG (1982) Effects of xylene and xylene isomers on cytochrome P-450 and in vitro enzymatic activities in rat liver, kidney and lung. Toxicology 23: 197–212
Tong SS, Hirokata Y, Trush MA, Mimaugh EG, Ginsburg E, Lowe MC, Gram TE (1981) Clara cell damage and inhibition of pulmonary mixed-function oxidase activity by naphthalene. Biochem Biophys Res Commu 100: 944–950
Tong SS, Lowe MC, Trush MA, Mimnaugh EG, Ginsburg E, Hirokata Y, Gram TE (1982) Bronchiolar epithelial damage and impairment of pulmonary microsomal monooxygenase activity in mice by naphthalene. Exp Mol Pathol 37: 358–369
Vainio H, Hietanen E (1980) Role of extrahepatic metabolism. In: Jenner P, Testa B (eds) Concepts in drug metabolism. Marcel Dekker, Inc., New York, Part A: pp 251–284
Vainiotalo S, Zitting A, Jacobsson S, Nickels J, Koskinen H, Savolainen H (1984) Toxicity of polymethylmethacrylate thermodegradation products. Arch Toxicol 55: 137–142
WHO (World Health Organization) (1981) Recommended health-based limits in occupational exposure to selected organic solvents: Xylene. WHO Tech Rep Ser 664, WHO Geneva, pp 25–37
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Elovaara, E., Zitting, A., Nickels, J. et al. m-Xylene inhalation destroys cytochrome P-450 in rat lung at low exposure. Arch Toxicol 61, 21–26 (1987). https://doi.org/10.1007/BF00324543
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DOI: https://doi.org/10.1007/BF00324543