Oxidation at C-1 controls the cytotoxicity of 1,1-dichloro-2,2- bis(p-chlorophenyl)ethane by rabbit and human lung cells.
Isolated rabbit Clara cells and a transformed human bronchial epithelial cell line, BEAS-2B, were used to investigate the mechanism of cytotoxicity of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD), a persistent insecticide and stable metabolite of 1,1,1-trichloro-2,2- bis(p-chlorophenyl)ethane. Both BEAS-2B cells and rabbit Clara cells were highly susceptible to DDD toxicity and were partially protected by 1-aminobenzotriazole, a suicide substrate inhibitor of cytochrome P450 enzymes. DDD (0.05 mM) killed 47 +/- 1.8% of rabbit Clara cells and 42 +/- 7.9% of BEAS-2B cells after 3 hr and 84 +/- 3.0% of rabbit Clara cells and 80 +/- 14% of BEAS-2B cells after 6 hr. Consequently, DDD is the most potent Clara cell toxicant recognized to date. The cytotoxicity of DDD to these cells was decreased by deuterium substitution at the C-1 position. Rabbit Clara cells and pulmonary microsomes incubated with 14C-DDD produced the fully oxidized acetic acid metabolite 2,2'-bis(p- chlorophenyl)acetic acid (DDA), but DDA was not formed by Clara cells when DDD was coincubated with 1-aminobenzotriazole. These results support the hypothesis that the cytotoxicity of DDD to susceptible subpopulations of rabbit and human lung cells is, at least in part, caused by cytochrome P450-mediated oxidation of DDD at C-1. A required step for the production of the cytotoxic intermediate is proposed to be the formation of a highly reactive acyl halide intermediate that is readily hydrolyzed to a stable, nontoxic metabolite, DDA.
Nichols
W K
WK
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112, USA.
Terry
C M
CM
Cutler
N S
NS
Appleton
M L
ML
Jesthi
P K
PK
Yost
G S
GS
D000818:Animals; D001711:Biotransformation; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D002250:Carbon Radioisotopes; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003634:DDT / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D003903:Deuterium; D003632:Dichlorodiphenyldichloroethane / Q000493:pharmacokinetics* / Q000633:toxicity*; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction; D011817:Rabbits; D014316:Tritium
D002250:Carbon Radioisotopes; D008934:Mitogens; D014316:Tritium; C000849:bis(p-chlorophenyl)acetic acid; D003903:Deuterium; D003634:DDT; D003632:Dichlorodiphenyldichloroethane