DNA adducts formation

DNA adducts can be formed as a result of covalent binding of hard electrophiles to DNA during bioactivation. For example, DNA adduct formation has been linked 

In addition to DNA adducts that occur as a result of covalent binding of reactive intermediates generated by oxidation or conjugation of parent compounds to DNA, reactive oxygen species produced during xenobiotic metabolism can also react with nucleophilic biomolecules. 

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I 97. Efarris, C. C. (1989). Interindividual variation. among humans in carcinogen metabolism, DNA adduct formation and DNA repair. Carcinogenesis 10, 1563-1566. 

Dubois M, Pfohl-Leszkowicz A, De Waziers I, etal. 1996. Selective induction of the cyp3a family by endosulfan and DNA-adduct formation in different hepatic and hepatoma cells. Environmental Toxicology and Pharmacology l(4) 249-256. 

Each plant tissue tends to have an obviously distinctive profile of flavonoids. The flavonoid content can reach about 0.5% in pollen, 10% in propolis, and about 6 mg/kg in honey. Havonoid aglycones appear to be present only in propolis and honey, while pollen contains flavanols in herosidic forms. The flavonoids in honey and propolis have been identified as flavanones and flavanones/flavanols (Campos et ah, 1990). The antimi-crobially active flavanone pinocembrine was foimd to be a major flavonoid in honey (Bogdanov, 1989). Amiot et ah (1989) studied two blossom and two honeydew Swiss honey samples and foimd that pinocembrine was the main flavonoid. Pinocembrine concentration varied between 2 and 3 mg/kg (Bogdanov, 1989). Berahia et ah (1993) analyzed sunflower honey samples and detected six flavone/flavols, four flavanone/ flavols, and pinocembrin, of which pinocembrin is the main flavonoid. The flavonoids in sunflower honey and propolis were characterized and assessed for their effects on hepatic drug-metabolizing enzymes and benzo [fl]pyrene-DNA adduct formation (Sabatier et ah, 1992 Siess et ah, 1996). 

Bodell, W. J. Ye, Q. Pathak, D. N. Pongracz, K. Oxidation of eugenol to form DNA adducts and 8-hydroxy-2 -deoxyguanosine role of quinone methide derivative in DNA adduct formation. Carcinogenesis 1998, 19, 437 143. 

Potter, G. A. McCague, R. Jarman, M. A mechanistic hypothesis for DNA adduct formation hy tamoxifen following hepatic oxidative metaholism. Carcinogenesis 1994,5, 439 142. 

Hayashi, N. Hasegawa, K. Barrett, J. C. Tsutsui, T. Estrogen-induced cell transformation and DNA adduct formation in cultured Syrian hamster embryo cells. Mol. Carcinog. 1996, 16, 149-156. 

Ni(salen)-DNA adduct formation is closely related to that formed by the Ni(peptide) systems, although there are different mechanisms proposed for both types of complexes. In the case of Ni(salen), the addition of a phenol radical to the guanine heterocycle and formation of a covalent bond to guanine C8 (Equation (9)) is suggested. 

Direct evidence for the importance of DNA adduct formation being one... 

The role of N-sulfonyloxy arylamines as ultimate carcinogens appears to be limited. For N-hydroxy-2-naphthylamine, conversion by rat hepatic sulfotransferase to a N-sulfonyloxy metabolite results primarily in decomposition to 2-amino-l-naphthol and 1-sulfonyloxy-2-naphthylamine which are also major urinary metabolites and reaction with added nucleophiles is very low, which suggests an overall detoxification process (9,17). However, for 4-aminoazobenzene and N-hydroxy-AAF, which are potent hepatocarcinogens in the newborn mouse, evidence has been presented that strongly implicates their N-sulfonyloxy arylamine esters as ultimate hepatocarcinogens in this species (10,104). This includes the inhibition of arylamine-DNA adduct formation and tumorigenesis by the sulfotransferase inhibitor pentachlorophenol, the reduced tumor incidence in brachymorphic mice that are deficient in PAPS biosynthesis (10,115), and the relatively low O-acetyltransferase activity of mouse liver for N-hydroxy-4-aminoazobenzene and N-OH-AF (7,114,115). 

The exceptional reactivity of DNA for protonated N-hydroxy arylamines can be rationalized by at least two mechanisms. First, intercalation of the electrophilic intermediate between DNA bases could sterically assist in desolvation and in directing the electrophilic center of the carcinogen over the nucleophilic region of the DNA base. This seems unlikely, however, as pretreatment of DNA with cis-Pt, which decreased the DNA contour length by 50%, failed to reduce the reactivity of N-hydroxy-1-naphthylamine for the DNA (137). A second possibility involves an electrostatic attraction between the electrophile and the phosphate backbone of the DNA (77). This seems more probable since eithe j +high ionic strength or stoichiometric (to DNA-P) amounts of Mg strongly inhibit DNA adduct formation (77,137). In addition, evidence has been presented that N-hydroxy arylamine-DNA/RNA phosphotriesters may be formed which induce strand breaks (137,138) and could serve as a catalyst for desolvation and subsequent adduct formation. 

Jung KJ, Wallig MA and Singletary KW. 2006. Purple grape juice inhibits 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation. Cancer Lett 233 279-288. 

Hypomethylation, as judged by loss of 5-methyl deoxycytidine content from DNA, occurred shortly after BaP exposure and continued upon termination of exposure conditions. Onset and persistence of hypomethylation were correlated with other types of DNA-damaging events, including strand breaks and DNA adduct formation... 

McElroy, A.E., J.M. Cahill, J.D. Sisson, and K.M. Kleinow. 1991. Relative bioavailability and DNA adduct formation of benzo[a]pyrene and metabolites in the diet of the winter flounder. Comp. Biochem. Physiol. 100C 29-32. 

Aflatoxin Bi (AFB) is a mold metabolite which has been observed to be acutely toxic and carcinogenic to a wide variety of animals (5,6) and has been implicated in human primary hepatic carcinoma (7, 8). Diets deficient in protein have been reported to increase the susceptibility of mammals to acute AFB toxicity and the induction of cancer (2, 9, 10, 11, 12, 13). Increased dietary proteins have increased the carcinogenic activity of AFB fed to rats (1 4) and trout (15.). Supportive of this latter finding has been the reported direct relationship between dietary protein content and AFB-DNA adduct formation in vivo in rats (16, 17). 

Wen X, and Walle T (2005) Preferential induction of CYP1B1 by benzo[a]pyrene in human oral epithelial cells Impact on DNA adduct formation and prevention by polyphenols. Carcingenesis 26 1774—1781. 

No evidence of exposure-related DNA adduct formation in femur bone marrow, Zymbal gland, liver, or spleen was seen in rats treated orally with 75 mg/kg/day phenol for 4 days (Reddy et al. 1990). In this study, concurrent in vitro exposures of these tissues did produce adducts, suggesting that efficient detoxification and excretion mechanisms may be operating in vivo. 

In mice, also, deacetylation is involved in the hepato-carcinogenesis induced by 2-(acetylamino)fluorene. Indeed, BNPP-inhibited DNA-adduct formation in murine liver microsomes as well as tumor initiation by A-hydroxy-2-(acetylamino)fluorene in infant male B6C3Fj mice [100],... 

A less invasive procedure that could provide a indication of DNA adduct formation is measurement in the urine of the mercaptic acid S-[2-N -guanl)ethyl]-N-acetylcysteine. Excretion of this metabolite into the urine of rats occurs in a dose-dependent, linear manner after intraperitoneal administration of 1,2-dibromoethane (Kim and Guengerich 1989). This biomarker has not been looked for to date in humans suspected to have exposure to 1,2-dibromoethane. 

Apart from gene silencing, other effects of DNA methylation include spontaneous deamination, enhanced DNA binding of carcinogens and increased UV absorption by DNA, all of which increase the rate of mutations, DNA adduct formation and subsequent gene inactivation... 

Y. Ueyama, Y. Monden, X. B. He, C. X. Lin, M. A. Momen, S. Mimura and A. Umemoto, Effects of bile acids on 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine-induced aberrant crypt foci and DNA adduct formation in the rat colon, J. Exp. Clin. Cancer Res., 2002, 21, 577. 

The term genotoxicity is a broader term and refers to potentially harmful effects on genetic material, which are not necessarily associated with mutagenicity. Thus, tests for genotoxicity include tests, which provide an indication of induced damage to DNA (but not direct evidence of mutation) via effects such as unscheduled DNA synthesis (UDS), sister chromatid exchange (SCE), DNA strand breaks, DNA adduct formation or mitotic recombination, as well as tests for mutagenicity. ... 

Daniel FB, Schut HAJ, Sandwisch DW, et al Interspecies comparisons of benzo[ ]pyrene metabolism and DNA-adduct formation in cultmed human and animal bladder and tracheobronchial tissues. Cancer Res MAI 2M 4729, 1983... 

Wilson PM, LA DK, Froines JR Hemoglobin and DNA adduct formation in Fischer-344 rats exposed to 2,4- and 2,6-toluene diamine. Arch Toxicol 70(10) 591-598, 1996... 

La DK, Lilly PD, Anderegg RJ, et al DNA adduct formation in B6C3F1 mice and Fischer-344 rats exposed to 1,2,3-trichloropropane. Carcinogenesis 16(6) 1419-1424, 1995... 

Johnson SW, Shen DW, Pastan I, Gottesman MM, Hamilton TC. Cross-resistance, cisplatin accumulation and platinum-DNA adduct formation and removal in cisplatin-sensitive and -resistant human hepatoma cell lines. Exp Cell Res 1996 226 133-139. 

Shellard SA, Fichtinger-Schepman AMJ, Lazo JS, Hill BT. Evidence of differential cisplatin DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines. Anti-Cancer Drugs 1993 4 491-500. 

Fichtinger-Schepman AMJ, Dijt FJ, De Jong WH, van Oosterom AR, Berends F. In vivo cis-diamminedichloroplatinum(II)-DNA adduct formation and removal as measured with immunochemical techniques. In (Nicolini M, ed), Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy 1988 Martinus Nijhoff Publishing Boston, pp. 32-46. 

Gupta-Burt S, Shamkhani H, Reed E, et al. Correlation between patient response in ovarian, breast, and colon cancer and platinum drug-DNA adduct formation. Cancer Epidem, Biomarkers Preven 1993 2 229-234. 

Schehens JH, Ma J, Planting AS, et al. Relationship between the exposure to cisplatin, DNA-adduct formation in leukocytes and tumorresponse inpatients with sohd tumors. BrJ Cancer1996 73 1569-1575. 

Using these patterns, it was possible to speculate on the preferred epoxidation sites and possible ring opening modes, which could induce similar charge delocalization paths. In relation to metabolic epoxidation and subsequent DNA adduct formation, these patterns pointed to the possible importance of K-region and M-region epoxides for some of the methano-PAHs. 

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