114378-32-4Relevant articles and documents
Expanded analysis of benzo[a]pyrene-DNA adducts formed in vitro and in mouse skin: Their significance in tumor initiation
Chen,Devanesan,Higginbotham,Ariese,Jankowiak,Small,Rogan,Cavalieri
, p. 897 - 903 (1996)
This paper reports expanded analyses of benzo[a]pyrene (BP)-DNA adducts formed in vitro by activation with horseradish peroxidase (HRP) or 3- methylcholanthrene-induced rat liver microsomes and in vivo in mouse skin. The adducts formed by BP are compared to those formed by BP-7,8-dihydrodiol and anti-BP diol epoxide (BPDE). First, activation of BP by HRP produced 61% depurinating adducts: 7-(benzo[a]pyrene-6-yl)guanine (BP-6-N7Gua), BP-6- C8Gua, BP-6-N7Ade, and the newly identified BP-6-N3Ade. As a standard, the last adduct was synthesized along with BP-6-N1Ade by electrochemical oxidation of BP in the presence of adenine. Second, identification and quantitation of BP-DNA adducts formed by microsomal activation of BP showed 68% depurinating adducts: BP-6-N7Ade, BP-6-N7Gua, BP-6-C8Gua, BPDE-10-N7Ade, and the newly detected BPDE-10-N7Gua. The stable adducts were mostly BPDE- 10-N2dG (26%), with 6% unidentified. BPDE-10-N7Ade and BPDE-10-N7Gua were the depurinating adducts identified after microsomal activation of BP-7,8- dihydrodiol or direct reaction of anti-BPDE with DNA. In both cases, the predominant adduct was BPDE-10-N2dG (90% and 96%, respectively). Third, when mouse skin was treated with BP for 4 h, 71% of the total adducts were the depurinating adducts BP-6-N7Gua, BP-6-C8Gua, BP-6-N7Ade, and small amounts of BPDE-10-N7Ade and BPDE-10-N7Gua. These newly detected depurinating diol epoxide adducts were found in larger amounts when mouse skin was treated with BP-7,8-dihydrodiol or anti-BPDE. The stable adduct BPDE-10-N2dG was predominant, especially with anti-BPDE. Comparison of the profiles of DNA adducts formed by BP, BP-7,8-dihydrodiol, and anti-BPDE with their carcinogenic potency indicates that tumor initiation correlates with the levels of depurinating adducts, but not with stable adducts. Furthermore, the levels of depurinating adducts of BP correlate with mutations in the Harvey- ras oncogene in DNA isolated from mouse skin papillomas initiated by this compound [Chakravarti et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 10422- 10426]. The depurinating adducts formed by BP in mouse skin appear to be the key adducts leading to tumor initiation.
Radical cations of benzo[a]pyrene and 6-substituted derivatives: Reaction with nucleophiles and DNA
Stack,Cremonesi,Hanson,Rogan,Cavalieri
, p. 755 - 760 (1995)
1. Oxidation of benzo[a]pyrene (BP) by I2 in the presence of AgClO4 in benzene generates the BP.+ ClO4- · AgI complex. This same method was used to produce radical cations from 6-FBP, 6-ClBP, 6-BrBP and 6-CH3BP. 2. Reaction of the BP,6-FBP,6-ClBP and 6-BrBP radical cation perchlorates with H2O produced BP 1,6-, 3,6- and 6,12- dione, whereas 6-CH3BP.+ClO4- · AgI yielded 6-CH2OHBP. 3. When BP.+ClO4- · AgI and 6-FBP.+ClO4- · AgI were reacted with NaOAc in H2O/CH3CN (9:1), 6-OAcBP was formed, in addition to the quinones. In the case of 6-CIBP.+ClO4- · AgI, a small amount of 1-OAc-6-ClBP and 3-OAc-6-ClBP was formed in, addition to the diones, whereas for 6-BrBP and 6-CH3BP the reaction products were BP diones and 6-CH2OHBP respectively. 4. These results confirm the localization of charge in the BP.+ at C-6, followed by C-1 and C-3. 5. The reaction of BP with NOBF4 in CH2Cl2 produced BP.+ BF4-, radical cation free of complexation with inorganic salts. 6. Reaction of BP.+BF4- with DNA produced the depurinating adducts BP-6-C8Gua, BP-6-C8dGua and BP-6-N7Gua.
Synthesis of adducts formed by iodine oxidation of aromatic hydrocarbons in the presence of deoxyribonucleosides and nucleobases
Hanson, Aaron A.,Rogan, Eleanor G.,Cavalieri, Ercole L.
, p. 1201 - 1208 (2007/10/03)
Polycyclic aromatic hydrocarbons (PAH) undergo two main pathways of metabolic activation related to the initiation of tumors: one-electron oxidation to give radical cations and monooxygenation to yield bay-region diol epoxides. Synthesis of standard adducts is essential for identifying biologically formed adducts. Until recently, radical cation adducts were synthesized by oxidation of the PAH in an electrochemical apparatus, not readily available in many organic chemistry laboratories. We have developed a convenient and efficient method for synthesizing PAH-nucleoside adducts by using I2 as the oxidant. Adducts of benzo[a]pyrene (BP), dibenzo[a,l]pyrene (DB[a,l]P), and 7,12-dimethylbenz[a]anthracene were synthesized with deoxyguanosine (dG), deoxyadenosine, guanine (Gua), or adenine in either Me2SO or dimethylformamide (DMF) with or without AgC104. When, for example, the potent carcinogen BP was dissolved in DMF in the presence of 3 equiv of I2, 5 equiv of dG, and 1 equiv of AgC104, 45% of the BP was converted to BP-6-N7Gua. When BP was placed under the same reaction conditions in the absence of AgC104, the extent of formation of BP-6-N7Gua decreased to 30%. When the potent carcinogen DB[a,l]P was dissolved in DMF in the presence of 3 equiv of I2, 5 equiv of dG, and 1 equiv of AgC104, 43% of the DB[a,l]P was converted to DB[a,l]P-10-N7Gua. In the more polar solvent Me2SO under the same reaction conditions, however, the yield of DB[a,l]P-10-N7Gua was only 20%. Synthesis of adducts with the oxidant I2 is more convenient and, in some cases, more efficient than synthesis by electrochemical oxidation. This method simplifies the synthesis of PAH-nucleoside and nucleobase adduces that are essential for studying biologically formed PAH-DNA adducts.
Synthesis an Identification of Benzopyrene-Guanine Nucleoside Adducts Formed by Electrochemical Oxidation and by Horseradish Peroxidase Catalyzed Reaction of Benzopyrene with DNA
Rogan, E. G.,Cavalieri, E. L.,Tibbels, S. R.,Cremonesi, P.,Warner, C. D.,et al.
, p. 4023 - 4029 (2007/10/02)
One-electron oxidation plays an important role in the metabolism of many substrates and their covalent binding to macromolecules.This mechanism of activation can be demonstrated by elucidation of the structure of DNA adducts.In this paper, we report the synthesis of adducts by anodic oxydation of benzolpyrene (BP) in the presence of deoxyguanosine (dG) or guanosine (G).By using 1H and two-dimensional NMR spectroscopy as well as fast atom bombardment and collisionally activated decomposition (CAD) mass spectroscopy, adducts were identified as BP bound at C-6-C-8 of guanine (Gua), dG and G and to N-7 of Gua.Loss of deoxyribose from the N-7 adduct was anticipated, but it was unexpectedly found that about 30percent of the C-8 adduct with dG lost the deoxyribose moiety.The C-8 adduct of G almost entirely retained the ribose moiety.These compounds were used as markers for high pressure liquid chromatography (HPLC) to identify adducts formed in the horseradish peroxidase catalysed binding of BP to DNA.By use of HPLC in two solvent systems, adducts were identified in the supernatant fraction obtained after ethanol precipitation of the DNA and in an enzymatic digest of the DNA.The supernatant, containing adducts lost by depurination, afforded 95percent of the N-7 adduct and about half of the C-8 adduct.The major adduct identified in the DNA digest was the C-8 of dG.The structure of the N-7 adduct in the supernatant was confirmed by CAD mass spectroscopy.These results demonstrate that horseradish peroxidase catalyzes binding of BP to DNA by one-electron oxidation.
