In vitro reactions of glycidol with pyrimidine bases in calf thymus DNA.
The 3-carbon epoxide glycidol (GLC) was reacted with dCyd and dThd at pH 7.0 to 7.5 and 37 degrees C for 10 h. The only product detected from the reaction with dCyd was 3-(2,3-dihydroxypropyl)-dUrd (3-DHP-dUrd) whose structure was established from UV spectra, isobutane chemical ionization (CI) mass spectra together with accurate mass measurements and synthesis of 3-DHP-dUrd from reactions of GLC with dUrd. Reaction of GLC with dThd gave a single product, 3-DHP-dThd, whose structure was established from UV spectra and CI mass spectra together with accurate mass measurements. The compounds, 3-DHP-dUrd and 3-DHP-dThd, were identified and quantitated following in vitro reaction of GLC with calf thymus DNA at pH 7.0 to 7.5 and 37 degrees C for 10 h. The amounts of 3-DHP-dUrd and 3-DHP-dThd formed were 10 and 1 nmol/mg DNA respectively. Alkylation at the N-3 position of Cyt resulted in a rapid hydrolytic deamination of Cyt to form a Ura adduct. This phenomena was previously reported by us following reaction of propylene oxide (PO) with dCyd and following in vitro reaction of PO with calf thymus DNA under identical conditions. The rapid hydrolytic deamination of Cyt to Ura may be a general occurrence following alkylation of N-3 of Cyt by 3-carbon epoxides and is postulated to be related to the presence of a C-2 hydroxyl group on the 3-carbon propyl side chain. The implications of this newly discovered lesion in DNA in terms of the mutagenicity of GLC (and PO) remain to be elucidated.
Segal
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Institute of Environmental Medicine, New York University School of Medicine, NY 10016.
Solomon
J J
JJ
Mukai
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D000433:1-Propanol / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D003841:Deoxycytidine / Q000378:metabolism; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D020005:Propanols; D011743:Pyrimidines / Q000378:metabolism*; D013936:Thymidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism*
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D020005:Propanols; D011743:Pyrimidines; D003841:Deoxycytidine; C063943:3-(2,3-dihydroxypropyl)deoxyuridine; D004247:DNA; C063944:3-(2,3-dihydroxypropyl)thymidine; D000433:1-Propanol; C004312:glycidol; D013936:Thymidine; D003857:Deoxyuridine