Formation of reactive 1-nitropyrene metabolites by lung microsomes and isolated lung cells.
The metabolism and activation of 1-nitropyrene (1-NP) to reactive intermediates by lung microsomes and isolated lung cells was studied. Mutagenicity of 1-NP metabolites was assayed in Salmonella typhimurium TA98NR, a strain lacking a major component of nitroreductase activity. In the presence of NADPH, microsomes from rabbit, rat and hamster lung metabolized 1-NP to mutagenic products to a similar degree. Pretreatment with a mixture of polychlorinated biphenyls (PCB) decreased the formation of mutagenic metabolites by rabbit lung microsomes, but did not affect the production of mutagens by rat or hamster lung microsomes. 3H-1-NP was metabolized to covalently bound protein products at a rate of 82 and 10 pmol/mg by rabbit and hamster lung microsomes, respectively, whereas no binding was detected in rat lung microsomes. PCB-pretreatment increased covalent protein binding of 3H-1-NP in lung microsomes from hamster and rat, but decreased the binding in rabbit lung microsomes. High performance liquid chromatography analysis indicated that 3H-1-NP was readily converted to ring-hydroxylated products by rabbit and hamster lung microsomes; the rate was much lower with rat lung microsomes. 3H-1-NP was activated to metabolites that covalently bound to protein in isolated rabbit lung cells, with the following rates being observed: Clara cells greater than lung digest greater than type II cells. In contrast, covalent protein binding in cells isolated from rat lung was very low. 1-NP was not activated to products mutagenic for S. typhimurium TA 98NR when co-incubated with cells isolated either from rabbit or rat lung.
Dybing
E
E
Department of Toxicology, National Institute of Public Health, Oslo, Norway.
Dahl
J E
JE
Beland
F A
FA
Thorgeirsson
S S
SS
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002469:Cell Separation; D066298:In Vitro Techniques; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D009152:Mutagenicity Tests; D009249:NADP / Q000378:metabolism; D011721:Pyrenes / Q000378:metabolism*; D011817:Rabbits
D002273:Carcinogens; D011721:Pyrenes; D009249:NADP; C032668:1-nitropyrene