Immunohistochemical Detection of Aflatoxin B 1 -DNA Adducts and Hepatitis B Virus Antigens in Hepatocellular Carcinoma and Nontumorous Liver Tissue

Santella, Regina M.; Zhang, Yujing; Chen, Chen-Jen; Hsieh, Ling‐Ling; Lee, Chue-Shue; Haghighi, Behzad; Yang, Guang-Yang; Wang, Lianwen; Feitelson, Mark A.

doi:10.2307/3431481

Cited by 7 publications

(46 citation statements)

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“…The NOESY connectivities through the adducted strand were disrupted by the presence of the aflatoxin lesion similar to that reported before (36). A number of characteristic NOEs were observed between the aflatoxin moiety and the 5′neighbor base pair, C 5 ‚G 16 . The aflatoxin H6a and H9a protons, facing the major groove, exhibited NOEs to C 5 H5.…”

Section: Discussionsupporting

confidence: 82%

“…It is linked to the etiology of human liver cancer (1) possibly via adduct-induced mutations in the p53 tumor suppresser gene (9)(10)(11)(12)(13)(14)(15) and ras protooncogenes (7,8) and probably exacerbated by co-infection by the hepatitis B virus (14,(16)(17)(18).…”

mentioning

confidence: 99%

“…Analysis of the rMD-Generated Structures of the AFB1 Adduct in the Mismatched AFB G‚A Pair 〈rMDB〉, average of 10 converged structures from B-DNA. ‚A 15 and C 5 ‚G16 . These two base pairs buckled in opposite directions away from the intercalated aflatoxin moiety.…”

mentioning

confidence: 99%

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Mispairing of the 8,9-Dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B₁ Adduct with Deoxyadenosine Results in Extrusion of the Mismatched dA toward the Major Groove

2002

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The G --> T transversion is the dominant mutation induced by the cationic trans-8,9-dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B(1) adduct. The structure of d(ACATC(AFB)GATCT).d(AGATAGATGT), in which the cationic adduct was mismatched with deoxyadenosine, was refined using molecular dynamics calculations restrained by NOE data and dihedral restraints obtained from NMR spectroscopy. Restrained molecular dynamics calculations refined structures with pairwise rmsd<1 A and a sixth root R1x factor between the refined structure and NOE data of 10.5 x 10-2. The mismatched duplex existed in a single conformation at neutral pH. The aflatoxin moiety intercalated above the 5' face of the modified (AFB)G. The mismatched dA was in the anti conformation about the glycosyl bond. It extruded toward the major groove and did not participate in hydrogen bonding with (AFB)G. The structure was compared with that of d(ACATCGATCT).d(AGATAGATGT) containing the corresponding unmodified G.A mismatch and with d(ACATC(AFB)GATCT).d(AGATCGATGT) containing the aflatoxin lesion in the correctly paired (AFB)G.C context. The correctly paired oligodeoxynucleotide exhibited Watson-Crick-type geometry at the (AFB)G.C pair. It melted at higher temperature than the mismatched (AFB)G.A duplex. The unmodified mismatched G.A duplex exhibited spectral line broadening at neutral pH, suggesting a mixture of conformations. It exhibited a lower melting temperature than did the mismatched (AFB)G.A duplex. These differences correlated with replication bypass experiments performed in vitro utilizing DNA polymerase I exo- [Johnston, D. S., and Stone, M. P. (2000) Chem. Res. Toxicol. 13, 1158-1164]. Those experiments showed that correct insertion of dC opposite (AFB)G blocked replication by the enzyme, whereas incorrect insertion of dA opposite (AFB)G allowed full-length replication of the adducted template strand.

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Section: Discussionsupporting

confidence: 82%

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confidence: 99%

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Mispairing of the 8,9-Dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B₁ Adduct with Deoxyadenosine Results in Extrusion of the Mismatched dA toward the Major Groove

2002

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“…AFB 1 is a mutagen in bacteria (2)(3)(4); it is carcinogenic in fish (5,6), and it is a hepatocarcinogen in rodents (7,8). It is linked to the etiology of human liver cancer (1) possibly via adduct-induced mutations in the p53 tumor suppresser gene (9)(10)(11)(12)(13)(14)(15) and ras proto-oncogenes (7,8) and probably exacerbated by coinfection by the hepatitis B virus (14,(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Refined Structure of the Doubly Intercalated d(TAT^AFBGCATA)₂ Aflatoxin B₁ Adduct

Jones

Johnston

Stone

1998

Chem. Res. Toxicol.

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The refined solution structure for the 8, 9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 adduct was refined from the oligodeoxynucleotide duplex d(TATAFBGCATA)2 using a molecular dynamics protocol restrained by NOE data obtained from 1H NMR and compared with the refined structure of the unmodified oligomer, d(TATGCATA)2. The two aflatoxin B1 (AFB1) moieties were symmetry related by the pseudodyad axis of the self-complementary oligodeoxynucleotide. Each AFB1 intercalated into the helix above the 5'-face of the modified guanine, corroborating NMR spectroscopic data [Gopalakrishnan, S., Harris, T. M., and Stone, M. P. (1990) Intercalation of Aflatoxin B1 in Two Oligodeoxynucleotide Adducts: Comparative 1H NMR Analysis of d(ATCAFBGAT).d(ATCGAT) and d(ATAFBGCAT)2 Biochemistry 29, 10438-10448]. Molecular dynamics calculations restrained with 292 experimentally and empirically derived distances refined a family of structures characterized by pairwise root mean square differences of <1.3 A. Complete relaxation matrix calculations yielded a sixth root residual of 11 x 10(-2). Comparison of the refined structure with that of the corresponding unmodified oligodeoxynucleotide suggested that the two AFB1 adducts introduced a perturbation of the DNA localized at the two sites of adduction. The calculations predicted that each adduct introduced a "kink" into the DNA helical axis. However, the pseudodyad symmetry relating the two intercalation sites resulted in no net bending of the DNA. The results suggest the possibility that AFB1 lesions at adjacent guanines in the 5'-GC-3' sequence may be recognized or processed differently than are isolated AFB1 lesions.

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“…Many DNA sequences of biological interest, including that of the p53 tumor suppressor gene, contain multiple guanines. Reports linking AFB 1 to site-specific transversion in the tumor suppressor gene p53 (5,6,(25)(26)(27)(28)(29), possibly exacerbated by co-infection by the hepatitis B virus (28,(30)(31)(32), made facile routes to these adducts important. The nonspecific reaction with AFB 1 -exo-8,9epoxide (10) was limited by the inability to control sequence selectivity in oligodeoxyribonucleotides containing multiple guanines.…”

Section: Introductionmentioning

confidence: 99%

Site-Specific Synthesis of Aflatoxin B₁ Adducts within an Oligodeoxyribonucleotide Containing the Human p53 Codon 249 Sequence

Jones

Johnston

Stone

1999

Chem. Res. Toxicol.

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This work describes the preparation of the cationic trans-8, 9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B(1) ((AFB)G) adducts at the positions corresponding to G(746) or G(747), within the oligodeoxyribonucleotide d(GGAGGCCT) containing the codon 249 sequence (underlined) of the p53 gene, using DNA triplexes to target adduction at the desired site. This approach enabled the successful preparation and purification of sufficient quantities of d(GGAG(AFB)GCCT) for NMR structural studies, using only standard phosphoramidites. The presence of multiple guanines in this oligodeoxynucleotide precluded the direct reaction of d(GGAGGCCT). d(AGGCCTCC) with aflatoxin epoxide as a method for producing large quantities of site-specific adducts for physical studies. Of the multiple potential alkylation sites at guanine N7 in d(GGAGGCCT). d(AGGCCTCC), it was found that sites G(2) and G(5) exhibited approximately equal reactivity with aflatoxin B(1)-exo-8,9-epoxide; the reactivity at site G(4) was reduced by approximately a factor of 2 as compared to that at G(2) or G(5). To successfully prepare the site-specific adducts, the p53 oligodeoxyribonucleotide was annealed with either the blocking strand d(CTCCATTTTCCT) or d(CCTCCATTTTCCTC) to form the corresponding partial triplexes which targeted AFB(1) adduction either to G(4) or to G(5). Piperidine cleavage, followed by heating, confirmed that in each instance, the product corresponded to the lone guanine not protected from adduction by the partial DNA triplex. The adducted oligodeoxyribonucleotides were examined with regard to purity by capillary electrophoresis. The primary advantage of this modified triple helix methodology is that it requires only standard phosphoramidites; thus, it is applicable to large-scale preparations that are necessary for NMR structural studies or other physical measurements.

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Immunohistochemical Detection of Aflatoxin B 1 -DNA Adducts and Hepatitis B Virus Antigens in Hepatocellular Carcinoma and Nontumorous Liver Tissue

Cited by 7 publications

References 2 publications

Mispairing of the 8,9-Dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B₁ Adduct with Deoxyadenosine Results in Extrusion of the Mismatched dA toward the Major Groove

Mispairing of the 8,9-Dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B₁ Adduct with Deoxyadenosine Results in Extrusion of the Mismatched dA toward the Major Groove

Refined Structure of the Doubly Intercalated d(TAT^AFBGCATA)₂ Aflatoxin B₁ Adduct

Site-Specific Synthesis of Aflatoxin B₁ Adducts within an Oligodeoxyribonucleotide Containing the Human p53 Codon 249 Sequence

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Immunohistochemical Detection of Aflatoxin B 1 -DNA Adducts and Hepatitis B Virus Antigens in Hepatocellular Carcinoma and Nontumorous Liver Tissue

Cited by 7 publications

References 2 publications

Mispairing of the 8,9-Dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B1 Adduct with Deoxyadenosine Results in Extrusion of the Mismatched dA toward the Major Groove

Mispairing of the 8,9-Dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B1 Adduct with Deoxyadenosine Results in Extrusion of the Mismatched dA toward the Major Groove

Refined Structure of the Doubly Intercalated d(TATAFBGCATA)2 Aflatoxin B1 Adduct

Site-Specific Synthesis of Aflatoxin B1 Adducts within an Oligodeoxyribonucleotide Containing the Human p53 Codon 249 Sequence

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Mispairing of the 8,9-Dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B₁ Adduct with Deoxyadenosine Results in Extrusion of the Mismatched dA toward the Major Groove

Mispairing of the 8,9-Dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B₁ Adduct with Deoxyadenosine Results in Extrusion of the Mismatched dA toward the Major Groove

Refined Structure of the Doubly Intercalated d(TAT^AFBGCATA)₂ Aflatoxin B₁ Adduct

Site-Specific Synthesis of Aflatoxin B₁ Adducts within an Oligodeoxyribonucleotide Containing the Human p53 Codon 249 Sequence