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© 1992 Oxford University Press

research-article

Effect of p-Xylene Inhalation on the Bioactivation of Bromobenzene in Rat Lung and Liver

BRIAN J. DAY*, DENNIS B. DENICOLA{dagger}, CRAIG B. MARCUS* and GARY P. CARLSON*

*Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacol Sciences, Purdue University West Lafayette, Indiana 47907 {dagger}Department of Veterinary Pathobiology, School of Veterinary Medicine, Purdue University West Lafayette, Indiana 47907

Received July 22, 1991; accepted November 13, 1991

It is unclear whether the pneumotoxicity observed with bromobenzene (BB) in phenobarbital-induced rats is related to BB bioactivation in lung, liver or both. To help differentiate pulmonary from hepatic bioactivation, BB was administered alone and in combination with/p-xylene, which inhibits pulmonary but induces hepatic cytochromes P450. Exposure to /vxylene alone (3400 ppm for 4 hr) produced no changes in bronchoalveolar lavage fluid (BALF) measurements ({gamma}-glutamyl transpeptidase, lactate dehydrogenase, protein, white blood cell count) or serum sorbitol dehydrogenase. p-Xylene increased hepatic microsomal benzyloxy- (BROD), pentoxy- (PROD), and ethoxy- (EROD) resorufin O-dealkylase activities but decreased pulmonary microsomal BROD and PROD. Immunoblot analysis revealed an induction of hepatic but not pulmonary microsomal P450IIB apoprotein. When rats were exposed to p-xylene (2800 ppm) or room air for 4 hr, treated 12 hr later with BB (0.5 ml/kg, ip) or corn oil, and killed after 12 hr, p-xylene increased hepatic P450IIB (27-fold) concomittant with a similar increase in BROD activity. p-Xylene also increased hepatic P450IA apoprotein (3.4-fold) with a complimentary increase in EROD activity. p-Xylene potentiated BB-induced hepatotoxicity. In pulmonary micro-somes p-xylene and BB each produced similar decreases in both EROD and BROD activities. The combination of p-xylene and BB had an additive effect on pulmonary P450IA1 reduction. BALF analysis and histopathology revealed no pneumotoxicity with any treatment. p-Xylene potentiation of BB-induced hepatotoxicity without pneumotoxicity suggests that the liver does not produce metabolites of BB which are directly involved in pulmonary damage.


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