Comparison of rat hepatic and pulmonary microsomal metabolism of benzene and the lack of benzene-induced pneumotoxicity and hepatotoxicity.
Since little is known about the toxicity of benzene in the lung or if the lung is capable of metabolizing benzene, the ability of the lung to bioactivate or detoxify benzene and the pneumotoxicity of benzene were determined. While overall metabolism was lower, pulmonary microsomes converted benzene (17.5 microM) to hydroquinone, considered to be a marker for benzene toxicity, in proportionately greater amounts than did hepatic microsomes. Treatment of rats with pyridine, an inducer of CYP2E1, enhanced hepatic microsomal metabolism of benzene, although benzene, which is also considered to be an inducer of CYP2E1, did not. Neither pyridine nor benzene treatment induced the pulmonary microsomal metabolism of benzene. When hepatic and pulmonary microsomes from control and pyridine-treated rats were incubated with benzene (17.5 microM) and the CYP2E1 inhibitor, diethyldithiocarbamate, benzene metabolism was significantly inhibited, indicating that CYP2E1 is the predominant cytochrome P-450 isozyme involved in hepatic and pulmonary metabolism in microsomes from control and pyridine-treated rats. Benzene (600 mg/kg body weight, i.p.) did not cause significant lung cell damage as determined by measurement of gamma-glutamyltransferase and lactate dehydrogenase in bronchoalveolar lavage fluid. Induction of CYP2E1 and CYP2B1/2 with pyridine and phenobarbital, respectively, did not alter this lack of effect. Thus, the primary concern about benzene and the lung should focus on benzene metabolism as opposed to acute toxicity.
Chaney
A M
AM
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907-1334, USA.
Carlson
G P
GP
D000818:Animals; D001554:Benzene / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004050:Ditiocarb / Q000494:pharmacology; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D002273:Carcinogens; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D009153:Mutagens; D011725:Pyridines; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D007064:L-Iditol 2-Dehydrogenase; D007770:L-Lactate Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D005723:gamma-Glutamyltransferase; D001554:Benzene; C023666:pyridine; C031927:hydroquinone