The effects of copollutants on the metabolism and DNA binding of carcinogens.
Copollutants found in air samples and other complex chemical mixtures may alter the metabolism, and thus the biological activity, of chemical carcinogens. As an initial step to determine whether the metabolism and DNA binding of carcinogenic nitrated polycyclic aromatic hydrocarbons found in diesel exhaust particles are altered by copollutants, we studied the effect of pyrene on the metabolism and DNA binding of 1-nitropyrene, and the effect of pyrene and 1-nitropyrene on the metabolism and DNA adduct formation of 1,6-dinitropyrene in male B6C3F1 mice. In in vitro incubations using liver microsomes from untreated mice, pyrene was a mixed-type inhibitor, with a 6.42-microM appKi. 2-Aminofluorene and 3-amino-2-methoxydibenzofuran were also effective inhibitors of 1-nitropyrene metabolism. Pyrene did not affect the total in vivo excretion of 1-nitropyrene when coadministered to mice at either a 10-fold or a 250-fold molar excess. At the higher dose of pyrene, however, the urinary excretion of 1-nitropyrene metabolites decreased by approximately 20%, whereas the concentration of fecal metabolites increased by the same amount. Similar in vivo experiments were conducted using 2-aminofluorene as the inhibitor. The excretion of 1-nitropyrene was not significantly affected by 2-aminofluorene treatment. Treatment-related DNA adducts were not detected by 32P-postlabeling analyses of liver DNA when 1-nitropyrene was administered by itself or with a 20- or 250-fold molar excess of pyrene. The coadministration of pyrene or 1-nitropyrene had no effect on the total excretion of 1,6-dinitropyrene metabolites. A single major adduct that coeluted with N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene was detected in hepatic DNA from mice treated with 1,6-dinitropyrene. The concentration of this adduct was significantly decreased by the coadministration of a 25-fold molar excess of pyrene and was significantly increased by simultaneous treatment with a 25-fold molar excess of 1-nitropyrene. These results demonstrate the effect of copollutants on potentially carcinogenic components of diesel exhaust and urban air.
Howard
P C
PC
Department of Environmental Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH.
Beland
F A
FA
D000393:Air Pollutants / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000032:analysis / Q000378:metabolism*; D004247:DNA / Q000032:analysis; D004195:Disease Models, Animal; D004336:Drug Antagonism; D005243:Feces / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010865:Pilot Projects; D011721:Pyrenes / Q000032:analysis / Q000378:metabolism*; D001335:Vehicle Emissions
D000393:Air Pollutants; D002273:Carcinogens; D011721:Pyrenes; D001335:Vehicle Emissions; D004247:DNA