Potentiation of bromobenzene-induced pneumotoxicity by phenobarbital as determined by bronchoalveolar lavage fluid analysis.
Bromobenzene produces pulmonary, renal and hepatic damage in the rat. Phenobarbital potentiates bromobenzene-induced hepatotoxicity. Studies were initiated to determine if phenobarbital potentiates the pulmonary damage produced by bromobenzene. In a dose ranging study, adult male rats were treated daily for 4 days with phenobarbital (80 mg/kg, ip) and on the fifth day were dosed with 0, 2, 3, or 4 mmoles/kg, ip, bromobenzene. In a larger study phenobarbital was given for 4 days (80 mg/kg, ip), and bromobenzene (3.3 mmoles/kg, ip) was given on the fifth day. Pulmonary damage was assessed 24 hours later in the first study and 12 hours later in the second study by bronchoalveolar lavage fluid analysis (BALF), microsomal mixed function oxidase measurements and histopathological evaluations. BALF biochemical markers employed were gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH) and total protein. Phenobarbital treatment greatly enhanced bromobenzene-induced GGT and LDH release into the lavage fluid in a dose-dependent manner. Phenobarbital treatment increased microsomal 7-O-dealkylation of both ethoxy- and pentoxyresorufin in the liver without affecting these activities in the lung. Bromobenzene treatment decreased the hepatic microsomal dealkylation of decreased the hepatic microsomal dealkylation of pentoxyresorufin in a dose-dependent manner. Since known rat pulmonary P450 isozymes have been reported to be insensitive to phenobarbital induction, it may be that the toxicity is due to transport of a reactive metabolite(s) formed in the liver to the lung or bromobenzene is activated by some other pulmonary P450 isozyme responsive to phenobarbital.
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.
B J
BJ
Day
D B
DB
DeNicola
G P
GP
Carlson
D000704:Analysis of Variance; D000818:Animals; D001969:Bromobenzenes / Q000008:administration & dosage / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000201:enzymology*; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007770:L-Lactate Dehydrogenase / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D010634:Phenobarbital / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D005723:gamma-Glutamyltransferase / Q000097:blood / Q000378:metabolism
D001969:Bromobenzenes; D003577:Cytochrome P-450 Enzyme System; C032036:bromobenzene; D010088:Oxidoreductases; D007770:L-Lactate Dehydrogenase; D019362:Cytochrome P-450 CYP2B1; D005723:gamma-Glutamyltransferase; D010634:Phenobarbital