Bioactivation of halogenated hydrocarbons by rabbit pulmonary cells.
1,1-Dichloro-2,2-bis (4'-chlorophenyl)ethane (DDD), 1,2-dibromoethane (DBE) and trichloroethylene are three halogenated hydrocarbons that selectively bind to pulmonary epithelial cells and that may be pneumotoxic. The susceptibility of pulmonary cells and the mechanisms of cytotoxicity of these compounds were evaluated using enriched subpopulations of isolated rabbit lung cells incubated with DDD, DBE, and trichloroethylene. These chlorinated and brominated hydrocarbons were studied to evaluate their ability to induce selective pneumotoxicity by their bioactivation in three cell types, i.e. Clara cells, alveolar type II cells, and alveolar macrophages. Evidence of cytochrome P-450 bioactivation was assessed by utilizing the suicide inhibitor, 1-aminobenzotriazole (ABT) to ameliorate cytotoxicity. DDD, DBE and trichloroethylene were cytotoxic to Clara cells, type II cells and alveolar macrophages and the order of cell susceptibility to DDD was Clara > type II > macrophages. DBE and trichloroethylene were nonselectively cytotoxic. ABT reduced the cytotoxic effects of DDD and DBE in Clara cells. These studies indicated that all three compounds were toxic to isolated lung cells and that bioactivation of DDD and DBE in rabbit Clara cells to a cytotoxic intermediate was mediated, at least in part, by cytochrome P-450 oxidation.
Nichols
W K
WK
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112.
Covington
M O
MO
Seiders
C D
CD
Safiullah
S
S
Yost
G S
GS
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003632:Dichlorodiphenyldichloroethane / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D015946:Ethylene Dibromide / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011817:Rabbits; D014230:Triazoles / Q000494:pharmacology; D014241:Trichloroethylene / Q000378:metabolism / Q000633:toxicity*
D014230:Triazoles; C033020:1-aminobenzotriazole; D015946:Ethylene Dibromide; D014241:Trichloroethylene; D003577:Cytochrome P-450 Enzyme System; D003632:Dichlorodiphenyldichloroethane