The goal on this project is to understand the relationship between carcinogen-DNA adducts, oncogenic mutations and initiation of cancer by polycyclic aromatic hydrocarbons (PAH) and catechol estrogens (CE). We have established a relationship between depurinating DNA adducts, which are released from DNA to leave apurinic sites, and the Harvey (h)-ras mutations exhibited by mouse skin papillomas induced by benzo[alpha]pyrene (BP), dibenzo[alpha,l)pyrene(DB[alpha,l]P), 7,12-dimethylbenz[alpha]anthracene (DMBA) and some of their metabolites. Specifically, depurinating adducts of Ade lead to A yields T transversions at codon 61 in ras and depurinating Gua adducts lead to G yields T transversions in codon 13. Presumably, the mutations are a consequence of mis-repaired apurinic sites generated by the loss of the depurinating adducts. Endogenous CE, metabolites of estrone (E1) and 17beta-estradiol (E2) that we hypothesize to be procarcinogens, can be oxidized to CE quinones (CE-Q) and bind to DNA. CE-3,4-Q form depurinating N7Gua adducts in abundance, generating apurinic sites in the DNA, which in vivo could be misrepaired to yield oncogenic mutations. To gain further evidence that H-ras mutations arise from depurinating adducts formed by PAH and CE-Q and to increase our understanding of sequence specificity in the formation of stable adducts and apurinic sits, we propose to (1) determine the H-ras mutations in mouse skin papillomas induced by selected PAH and correlate the mutations with adducts; (2) investigate whether H-ras mutations can be detected in preneoplastic mouse skin treated with DB[alpha l)P or DB[alphal]P-11,12-dihydrodiol; (3) analyze the stable and depurinating adducts formed in 18-bp oligonucleotides by treatment with CE-Q; (4) identify the nature of the DNA lesions (i.e., stable adducts or apurinic sites) in (a) a 231 base-pair region of pBR322 DFNA and (b) the exon 1 and 2 region (547 base-pairs) of c-H-ras induced by treatment with BPDE, DB[alphal]PDE, CE-Q or peroxidase- activated BP, DB[alpha,l]P or CE; and (5) analyze the mutations induced in the supF gene replicated by a HeLa cell extract after treatment with BPDE, DB[alpha,l]PDE, CE-Q or peroxidase-activated BP, DB[alpha,l]P or CE. The results of these studies will provide us with detailed knowledge of the reaction of the selected PAH and CE-Q with DNA to generate apurinic sites, stable adducts and oncogenic mutations.
| Cavalieri, Ercole; Saeed, Muhammad; Zahid, Muhammad et al. (2012) Mechanism of DNA depurination by carcinogens in relation to cancer initiation. IUBMB Life 64:169-79 |
| Zahid, Muhammad; Saeed, Muhammad; Rogan, Eleanor G et al. (2010) Benzene and dopamine catechol quinones could initiate cancer or neurogenic disease. Free Radic Biol Med 48:318-24 |
| Saeed, Muhammad; Rogan, Eleanor; Cavalieri, Ercole (2009) Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: the defining link to natural estrogens. Int J Cancer 124:1276-84 |
| Saeed, Muhammad; Higginbotham, Sheila; Gaikwad, Nilesh et al. (2009) Depurinating naphthalene-DNA adducts in mouse skin related to cancer initiation. Free Radic Biol Med 47:1075-81 |
| Gaikwad, Nilesh W; Yang, Li; Muti, Paola et al. (2008) The molecular etiology of breast cancer: evidence from biomarkers of risk. Int J Cancer 122:1949-57 |
| Chakravarti, Dhrubajyoti; Venugopal, Divya; Mailander, Paula C et al. (2008) The role of polycyclic aromatic hydrocarbon-DNA adducts in inducing mutations in mouse skin. Mutat Res 649:161-78 |
| Lu, Fang; Zahid, Muhammad; Wang, Cheng et al. (2008) Resveratrol prevents estrogen-DNA adduct formation and neoplastic transformation in MCF-10F cells. Cancer Prev Res (Phila Pa) 1:135-45 |
| Zahid, Muhammad; Saeed, Muhammad; Lu, Fang et al. (2007) Inhibition of catechol-O-methyltransferase increases estrogen-DNA adduct formation. Free Radic Biol Med 43:1534-40 |
| Gaikwad, Nilesh W; Rogan, Eleanor G; Cavalieri, Ercole L (2007) Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones. Free Radic Biol Med 43:1289-98 |
| Zahid, Muhammad; Gaikwad, Nilesh W; Rogan, Eleanor G et al. (2007) Inhibition of depurinating estrogen-DNA adduct formation by natural compounds. Chem Res Toxicol 20:1947-53 |
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