DNA binding by 1-nitropyrene and dinitropyrenes in vitro and in vivo: effects of nitroreductase induction.
1-Nitropyrene, the predominant nitropolycyclic aromatic hydrocarbon found in diesel exhaust, is both a mutagen and a tumorigen. 1,6-Dinitropyrene is present in diesel exhaust in much smaller quantities than is 1-nitropyrene, but is much more mutagenic and carcinogenic. In an attempt to understand this difference in biological potencies, we have compared the extents to which these two nitropyrenes bind DNA in vivo. We have also determined the effect of 1-nitropyrene pretreatment upon the induction of nitroreductases and the subsequent DNA binding by both 1-nitropyrene and 1,6-dinitropyrene. In subsequent experiments, we have examined the importance of acetylation phenotype in the formation of DNA adducts from dinitropyrene in vivo. After a single intraperitoneal injection of 1-nitropyrene, covalent DNA binding could not be detected in vivo; however, 1,6-dinitropyrene formed N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene as the major DNA adduct in rat liver, kidney, urinary bladder, and mammary gland, with the highest levels being found in the bladder. The capability of liver microsomes to catalyze the oxidative metabolism of 1-nitropyrene was unchanged after treating rats with a single dose of 8 mg of 1-nitropyrene per kilogram of body weight. Cytochrome P-450, reduced nicotinamide adenine dinucleotide phosphate (NADPH2)-cytochrome P-450 reductase, and cytochrome b5 levels were also unchanged, while slight increases were detected in reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase and epoxide hydrase activities. Liver cytosolic and microsomal nitroreductase activities toward both 1-nitropyrene and 1,6-dinitropyrene were increased twofold, and cytosolic nitrosoreductase activity toward 1-nitrosopyrene and 1-nitro-6-nitrosopyrene was elevated by about 20 percent. DNA binding of both 1-nitropyrene and 1,6-dinitropyrene in vitro was twofold higher when cytosol from rats pretreated with 1-nitropyrene was used. However, pretreatment of rats with 1-nitropyrene only slightly increased the amount of in vivo DNA binding by 1,6-dinitropyrene except in the kidney, where there was a 60 percent increase. In the presence of S-acetylcoenzyme A, liver cytosol from slow-acetylator phenotype hamster strains Bio. 1.5 and 82.73 catalyzed the binding of two-to-three times more 1,8-dinitropyrene to DNA than was observed with the fast-acetylator phenotype strain Bio. 87.20. Similarly, when 1,8-dinitropyrene was administered in vivo and the extent of binding was assayed in liver, bladder, and intestinal DNA, there was more binding in strain Bio. 1.5 than in strain Bio. 87.20.(ABSTRACT TRUNCATED AT 400 WORDS)
Beland
F A
FA
University of Arkansas for Medical Sciences, Little Rock 72205.
D000818:Animals; D006224:Cricetinae; D003600:Cytosol / Q000201:enzymology; D004247:DNA / Q000378:metabolism*; D004790:Enzyme Induction; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D009601:Nitroreductases / Q000096:biosynthesis* / Q000378:metabolism; D010088:Oxidoreductases / Q000096:biosynthesis*; D011721:Pyrenes / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D011721:Pyrenes; C033309:1,6-dinitropyrene; D004247:DNA; D010088:Oxidoreductases; D009601:Nitroreductases; C032668:1-nitropyrene