Formation of reactive 1-nitropyrene metabolites by lung microsomes and isolated lung cells |
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Authors: | Dr Erik Dybing Jon E Dahl Frederick A Beland Snorri S Thorgeirsson |
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Institution: | (1) Department of Toxicology, National Institute of Public Health, Oslo, Norway;(2) Department of Toxicology, National Institute of Public Health, Geitmyrsveien 75, 0462 Oslo 4, Norway;(3) National Center for Toxicological Research, Jefferson, Arkansas;(4) Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, Maryland |
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Abstract: | 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 3 H-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 > lung digest > 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 98 N R when co-incubated with cells isolated either from rabbit or rat lung.Abbreviations 1-AP
1-aminopyrene
- DMSO
dimethyl sulfoxide
- EGTA
ethylene glycol-bis(ß-aminoethyl ether)
- EM
electron microscopy
- HEPES
N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid
- HPBS
HEPES-phosphate-buffered-saline
- HPLC
high performance liquid chromatography
- NBT
nitroblue tetrazolium
- 1-NP
1-nitropyrene
- 1-NP-4,5-diol
trans-4,5-dihydro-4,5-dihydroxy-1-nitropyrene
- 1-NP-9,10-diol
trans-9,10-dihydro-9,10-dihydroxy-1-nitropyrene
- 1-NP-4,5-oxide
1-nitropyrene-4,5-oxide
- 1-NP-9,10-oxide
1-nitropyrene-9,10-oxide
- 3-OH-1-NP
3-hydroxy-1-nitropyrene
- 6-/8-OH-1-NP
a mixture of 6- and 8-hydroxy-1-nitropyrene
- PBS
phosphate-buffered saline
- PCB
a mixture of polychlorinated biphenyls (Aroclor 1254)
- TLC
thin layer chromatography |
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Keywords: | isolated lung cells lung metabolism metabolic activation mutagenicity 1-nitropyrene |
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