In vivo DNA adduct formation by bisphenol A.
We have previously shown that bisphenol A (BPA) is oxidized to bisphenol-o-quinone in the presence of activation system and that the chemical reaction of DNA or deoxyguanosine 3'-monophosphate (dGMP) with bisphenol-o-quinone produces adducts. In the present study, using the 32P-postlabeling technique, we have investigated the in vivo DNA adduct formation by BPA by examining covalent modification in DNA. Administration of a single or multiple dose of 200 mg/kg of BPA to CD1 male rats produced two major and several minor adducts in liver DNA. The two major in vivo adducts matched the adduct profile of DNA or dGMP-bisphenol-o-quinone. To determine how BPA may be converted to DNA-binding metabolites, adducts were examined after incubation of DNA with BPA in the presence of a microsomal activation system. The in vitro incubation of BPA with DNA in the presence of a microsomal activation system revealed one major adduct and several minor adducts. The formation of adducts in DNA by BPA in the presence of a microsomal activation system was drastically decreased by known inhibitors of cytochrome P450. Adduct formation in DNA when cumene hydroperoxide or NADPH was used as a cofactor showed adducts with similar chromatographic mobilities as those from the reaction of dGMP-bisphenol-o-quinone. These data demonstrate that BPA is capable of binding covalently to DNA. DNA binding can be inhibited by the inhibitors of cytochrome P450. One of the DNA-binding metabolite(s) both in vitro and in vivo may be bisphenol-o-quinone. Covalent modifications in DNA by in vivo exposure of BPA may be a factor in the induction of hepatotoxicity.
Atkinson
A
A
Department of Environmental Health Science, University of Alabama, Birmingham 35294-008, USA.
Roy
D
D
D000818:Animals; D001559:Benzhydryl Compounds; D001711:Biotransformation; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D003848:Deoxyguanine Nucleotides / Q000737:chemistry; D004355:Drug Stability; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000378:metabolism*; D010761:Phosphorus Radioisotopes; D051381:Rats; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004247:DNA; D018736:DNA Adducts; D003848:Deoxyguanine Nucleotides; D009153:Mutagens; D010636:Phenols; D010761:Phosphorus Radioisotopes; C007257:2'-deoxyguanosine 5'-phosphate; C006780:bisphenol A; D000098826:Bisphenol A Compounds