Synthesis and liquid chromatography/tandem mass spectrometric characterization of the adducts of bisphenol A o-quinone with glutathione and nucleotide monophosphates.
An environmental, estrogen-like substance, bisphenol A (BPA), is the monomer for the production of polycarbonate plastics used in baby bottles, dental sealants, and as a major component of epoxy resin for the lining of food cans. The oxidation 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 aqueous acetic acid, BPA-Q also reacts with 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) but not with 2'-deoxycytidine and 2'-deoxythymidine. The reactions are accompanied by loss of the modified base (depurination). We determined the structures of the modified bases by primarily tandem mass spectrometry. In mixtures of deoxynuclesides and deoxynucletides 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 mixture. We also found that BPA-Q reacts readily with glutathione (GSH) under acidic or neutral conditions, and we 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. The adducts reported will also be appropriate references for identification of BPA-Q adducts in environmental and biological systems.
Department of Chemistry, Box 1134, Washington University, One Brookings Drive, St. Louis, Missouri 63130, USA.
Sheng-Xiang
SX
Qiu
Richard Z
RZ
Yang
Michael L
ML
Gross
D000395:Air Pollutants, Occupational / Q000737:chemistry; D001559:Benzhydryl Compounds; D016227:Benzoquinones / Q000737:chemistry*; D018736:DNA Adducts / Q000138:chemical synthesis / Q000737:chemistry*; D003854:Deoxyribonucleotides / Q000737:chemistry*; D015226:Dinucleoside Phosphates / Q000737:chemistry; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry*; D000098826:Bisphenol A Compounds
D000395:Air Pollutants, Occupational; D001559:Benzhydryl Compounds; D016227:Benzoquinones; D018736:DNA Adducts; D003854:Deoxyribonucleotides; D015226:Dinucleoside Phosphates; D005978:Glutathione; D009692:Nucleic Acid Heteroduplexes; D010636:Phenols; C487806:bisphenol A 3,4-quinone; D000098826:Bisphenol A Compounds