Potentiation of carbon tetrachloride-induced hepatotoxicity and pneumotoxicity by pyridine.
Induction of P450IIE1 by pyridine was compared with that by ethanol, and the resulting potentiation of the pneumotoxicity and hepatotoxicity following carbon tetrachloride inhalation by pyridine was examined. Rats were treated with ethanol as either a 10% solution in the drinking water or as a daily bolus (3 ml/kg, ip) dose for 7 days or one bolus dose of pyridine (200 mg/kg, ip) and compared for P450IIE1 apoprotein content by immunoblot analysis. Ethanol in the drinking water and pyridine elevated both hepatic and pulmonary P450IIE1 apoprotein content, but bolus dose ethanol did not. The induction was greatest in the pyridine group. In the interaction study, rats were treated with pyridine (200 mg/kg, ip) and 12 hours later were exposed to CCl4 (8000 ppm for 3 hours). Pulmonary injury and hepatic damage were assessed 24 hours later by bronchoalveolar lavage fluid (BALF) analysis [gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), and total protein] and serum sorbitol dehydrogenase (SDH) activity, respectively. Pyridine alone had no effect on BALF or SDH but enhanced GGT and LDH release into the BALF and SDH release into the serum when compared with CCl4 exposure alone. Evaluation of the liver at the light microscopic level revealed characteristic CCl4-induced centrilobular necrosis which was potentiated by pyridine. No changes were observed in the lung by light microscopic evaluation. Pyridine induced pulmonary and hepatic microsomal apoprotein levels of cytochrome P450IIE1 two- and 2- to sixfold, respectively. Exposure to CCl4 decreased hepatic but not pulmonary P450IIE1 levels. Induction of cytochrome P450IIE1 by pyridine increases the bioactivation of CCl4 in both the liver and lung, leading to enhanced toxicity.
Day
B J
BJ
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.
Carlson
G P
GP
DeNicola
D B
DB
D000280:Administration, Inhalation; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D000431:Ethanol / Q000633:toxicity; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D011725:Pyridines; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D007064:L-Iditol 2-Dehydrogenase; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase