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DNA Binding by 1-Nitropyrene and Dinitropyrenes In vitro and In vivo: Effects of Nitroreductase Induction

机译:1-硝基丙烯和二硝基丙烯在体外和体内的DNa结合:硝基还原酶诱导的影响

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The study compared the extents to which 1-nitropyrene (1-NP) and 1,6-dinitropyrene (1,6-DNP) bind DNA in vivo, determined the effect of 1-NP pretreatment on induction of nitroreductases and subsequent DNA binding by both 1-NP and 1,6-DNP, and examined the importance of acetylation phenotype in the formation of DNA adducts from DNP in vivo. After a single intraperitoneal injection of 1-NP, covalent DNA binding was not detected in vivo; 1,6-DNP 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 in the bladder. The capability of liver microsomes to catalyze the oxidative metabolism of 1-NP was unchanged. Cytochrome P-450, NADPH-cytochrome P-450 reductase, and cytochrome b5 levels were unchanged; NADH-cytochrome b5 reductase and epoxide hydrase activities increased slightly. Liver cytosolic and microsomal nitroreductase activities toward 1-NP and 1,6-DNP increased twofold, and cytosolic nitrosoreductase activity toward 1-nitrosopyrene and 1-nitro-6-nitrosopyrene increased by about 20 percent. DNA binding of 1-NP and 1,6-DNP in vitro was twofold higher in cytosol from rats pretreated with 1-NP. However, pretreatment of rats with 1-NP only slightly increased the amount of in vivo DNA binding by 1,6-DNP except in the kidney. 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 (1,8-DNP) to DNA than was observed with the fast-acetylator phenotype strain Bio. 87.20. When 1,8-DNP was administered in vivo, there was more DNA binding in strain Bio. 1.5 than in strain Bio. 87.20. A similar relationship was observed in mice. Thus, although nitroreduction is involved in DNA adduct formation by 1,6- and 1,8-DNP, other factors limit the extent of DNA binding in vivo.

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