Wk. Nichols et al., OXIDATION AT C-1 CONTROLS THE CYTOTOXICITY OF 1,1-DICHLORO-2,2-BIS(P-CHLOROPHENYL)ETHANE BY RABBIT AND HUMAN LUNG-CELLS, Drug metabolism and disposition, 23(5), 1995, pp. 595-599
Isolated rabbit Clara cells and a transformed human bronchial epitheli
al cell line, BEAS-2B, were used to investigate the mechanism of cytot
oxicity of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD), a persist
ent insecticide and stable metabolite of 1,1,1-trichloro-2,2-bis(p-chl
orophenyl) ethane. Both BEAS-2B cells and rabbit Clara cells were high
ly susceptible to DDD toxicity and were partially protected by 1-amino
benzotriazole, a suicide substrate inhibitor of cytochrome P450 enzyme
s. 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 m
ost potent Clara cell toxicant recognized to date, The cytotoxicity of
DDD to these cells was decreased by deuterium substitution at the C-l
position, Rabbit Clara cells and pulmonary microsomes incubated with
C-14-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 sup
port the hypothesis that the cytotoxicity of DDD to susceptible subpop
ulations of rabbit and human lung cells is, at least in part, caused b
y cytochrome P450-mediated oxidation of DDD at C-1. A required step fo
r the production of the cytotoxic intermediate is proposed to be the f
ormation of a highly reactive acyl halide intermediate that is readily
hydrolyzed to a stable, nontoxic metabolite, DDA.