Effect of p-xylene inhalation on the bioactivation of bromobenzene in rat lung and liver.
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 p-xylene 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) resorfuin 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 microsomes 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.
Day
B J
BJ
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
DeNicola
D B
DB
Marcus
C B
CB
Carlson
G P
GP
D000280:Administration, Inhalation; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation / Q000187:drug effects; D001969:Bromobenzenes / Q000493:pharmacokinetics* / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008171:Lung Diseases / Q000139:chemically induced; D008297:Male; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014992:Xylenes / Q000494:pharmacology*
D001969:Bromobenzenes; D014992:Xylenes; C031286:4-xylene; C032036:bromobenzene