This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The relative reactivity of 1,2-naphthoquinone in adduction to model ODNs, 6mer T-rich synthetic DNAs, was evaluated in our experiments with electrospray ionization mass spectrometry. Although the toxic mechanism of naphthalene in mammalian systems is still not fully understood, 1,2-naphthoquinone, which was generated by catalysis of cytochrome P450 as a metabolite of naphthalene, was believed to lead to the toxic effect of naphthalene because of its high electrophilicity. The depurinating reaction between 1,2-naphthoquinone and nucleobases, guanine/adenine in the sequence of a T-rich ODNs was proved by the observation of 1,2-naphthoquinoe-Ade/Gua adducts and depurinating ODNs [M-base+H2O]. Micromass Q-TOF was involved in the quantification of ODNs with internal calibration. An environmental, estrogen-like substance, bisphenol A (BPA), is the monomer for various consumer products. The oxidn. of BPA leads to the reactive electrophilic BPA-o-3,4-quinone (BPA-Q), which can damage DNA and may be implicated in cancer initiation. BPA-Q reacts in vitro with 2'-deoxyguanosine 5'-phosphate (dGMP) and 2'-deoxyadenosine 5'-phosphate (dAMP) but not with 2'-deoxycytidine-5'-phosphate and 2'-deoxythymidine 5'-phosphate. In aq. acetic acid, BPA-Q also reacts with 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) but not with 2'-deoxycytidine and 2'-deoxythymidine. In mixts. of deoxynucleosides and deoxynucleotides treated with BPA-Q, reactions occur more readily with dGMP/dG followed by dAMP/dA. With calf thymus DNA, significant apurinic sites must be produced because we detected the BPA-Q-guanosine adduct in the incubation mixt. We also found that BPA-Q reacts readily with glutathione (GSH) under acidic or neutral conditions and characterized the BPA-Q-GSH conjugate with tandem mass spectrometry (MS/MS). The results are consistent with a mechanism of carcinogenesis whereby BPA-Q, formed in vivo and not adequately detoxified by reactions with GSH, reacts with DNA, causing depurination.
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