Detection and characterization of DNA adducts formed from metabolites of the fungicide ortho-phenylphenol.
The significance of DNA adduction in ortho-phenylphenol-induced carcinogenesis remains unclear. Establishing adduct structures may contribute to resolving this issue. The chemical structures of the DNA adduction products resulting from the in vitro reaction of phenylbenzoquinone, the putative ultimate carcinogenic metabolite of the fungicide/disinfectant ortho-phenylphenol, are reported here. Three isomeric adducts that resulted from reaction of deoxyguanosine were characterized by UV, LC-ESI-MS, and MS/MS, and 1D and 2D COSY-NMR spectroscopy. The proposed mechanism of product formation is nucleophilic attack by the deoxyguanosine exocyclic amine nitrogen on an electrophilic quinone carbon, followed by stabilization through enolization. Another nucleophilic attack forms a five-membered ring, which aromatizes by dehydration to form the final product. Adducts were also characterized from deoxyadenosine and deoxycytidine, although conversions were at least 10 times lower. Structures are also proposed for these products. Cell culture studies confirmed that HepG2 cells incubated with phenylbenzoquinone at concentrations associated with cytotoxicity form the same DNA adducts.
Zhao
Shouxun
S
Department of Environmental Health and Toxicology, State University of New York at Albany, Wadsworth Center C236, Albany, New York 12201-0509, USA.
Narang
Amarjit
A
Gierthy
John
J
Eadon
George
G
D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000378:metabolism* / Q000494:pharmacology; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000032:analysis* / Q000737:chemistry; D003849:Deoxyguanosine / Q000737:chemistry; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013056:Spectrophotometry, Ultraviolet; D014407:Tumor Cells, Cultured
D016227:Benzoquinones; D001713:Biphenyl Compounds; D002273:Carcinogens; D018736:DNA Adducts; C029322:phenylbenzoquinone; C004369:2-phenylphenol; D003849:Deoxyguanosine