Time-dependent effects of o-xylene on rat lung and liver microsomal membrane structure and function.
The present study investigates the time-dependent effect of acute intraperitoneal o-xylene administration (1 g/kg) on rat hepatic and pulmonary mixed-function oxidase (MFO) content and activity and microsomal membrane structural parameters for up to 12 h postadministration. The purpose of this study was to determine whether o-xylene has similar effects on these parameters as those previously observed for the m and p isomers. o-xylene decreased total pulmonary cytochrome P-450 content and aryl hydrocarbon hydroxylase (AHH) activity at all time points examined with maximal inhibition occurring at 3 h postdose. The isozyme-specific MFO activity responsible for AHH activity was examined using benzyloxyresorufin O-dealkylation (BROD) as a measure of CYP2B1 activity and ethoxyresorufin O-dealkylation (EROD) as a measure of CYP1A1 activity. Reduced pulmonary activity for both EROD and BROD was noted for the 12-h postexposure period, in agreement with the decreases in total cytochrome P-450 content and AHH activity data. In contrast, increased hepatic cytochrome P-450 content was noted at 6 and 12 h with slightly increased EROD activity and markedly increased BROD activity. Conjugated diene (CD) formation, and index of membrane peroxidation, and phospholipid (PL) and cholesterol (CL) content of the microsomal membranes were also examined in lung and liver to assess membrane structural integrity. Pulmonary CD formation was increased only at the 12-h time point, while hepatic CD formation was increased from 3 to 12 h. An increase in pulmonary microsomal PL and CL content was noted as early as 1 h postdose. In liver, PL content was increased as early as 3 h, with no change in CL content. An increase in the PL/CL ratio, suggesting an increase in membrane fluidity, was observed in pulmonary microsomes 12 h after dosing, and in hepatic microsomes at 3, 6, and 12 h postdose. There was no correlation between solvent tissue levels and MFO or membrane changes. It seems unlikely that the lipid changes are causal in the observed o-xylene-induced MFO alterations, since they precede membrane lipid changes. Further, MFO activity decreases in lung and increases in liver, whereas lipid parameters increase in both organs. While these data may indicate an organ-selective difference in the relationship between membrane lipid changes and MFO activity, it is more likely that these lipid changes represent alternate toxicological effects of o-xylene. The results of this study indicate that the metabolism of other xenobiotics may be altered in o-xylene-exposed individuals in an organ-selective fashion.
Park
S H
SH
Toxicology Program, Northeastern University, Boston, Massachusetts 02115.
AuCoin
T A
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Silverman
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Schatz
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RA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007425:Intracellular Membranes / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014992:Xylenes / Q000097:blood / Q000494:pharmacology*
D014992:Xylenes; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C026114:2-xylene