Reaction of epichlorohydrin with 2'-deoxynucleosides: characterization of adducts.
Epichlorohydrin (ECH) is a simple 3-carbon epoxide of industrial importance and thus has the potential for human exposure in the workplace. It has been shown to be genotoxic in several systems and is a compound capable of reacting with biological nucleophiles. This study details the products formed from the reaction of ECH with 2'-deoxynucleosides at pH 7 and 37 degrees C for 6 h. Reaction with 2'-deoxyguanosine yielded 7-(3-chloro-2-hydroxypropyl) guanine (7-CHP-Gua) resulting from alkylation at N-7 of 2'-deoxyguanosine followed by depurination. Two unusual adducts were also partially characterized which resulted from further reaction of 7-CHP-Gua with another molecule of ECH to yield 1,7-bis(3-chloro-2-hydroxypropyl)guanine (1,7-bis-CHP-Gua) which could then cyclize with the exocyclic amino group to yield 1,N2-(2-hydroxypropano)-7-(3-chloro-2-hydroxypropyl) guanine (1,N2-HP-7-CHP-Gua). Reaction with 2'-deoxyadenosine gave only one product, namely 1,N6-(2-hydroxypropano)-2'-deoxyadenosine (1,N6-HP-dAdo). The reaction of 2'-deoxythymidine with ECH also yielded one product which was identified as 3-(3-chloro-2-hydroxypropyl)-2'-deoxythymidine (3-CHP-dThd). A 3-(3-chloro-2-hydroxypropyl)-2'-deoxyuridine (3-CHP-dUrd) product was isolated from the reaction of ECH with 2'-deoxycytidine. This product most likely resulted from the deamination of an initially formed 3-(3-chloro-2-hydroxypropyl) -2'-deoxycytidine (3-CHP-dCyd), a phenomenon which we have previously reported to occur during the reaction of 2'-deoxycytidine with other aliphatic epoxides. Evidence is also presented that 3-CHP-dUrd is converted to 3-(2,3-dihydroxypropyl)-2'deoxyuridine (3-DHP-dUrd) under physiological conditions, with a half-life of 213 h. Reaction of ECH with calf thymus DNA (pH 7.0, 37 degrees C, 3 h) resulted in the formation of 7-CHP-Gua (200 nmol/mg DNA.
Singh
U S
US
Department of Environmental Medicine, New York University Medical Center, NY 10016, USA.
Decker-Samuelian
K
K
Solomon
J J
JJ
D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D003839:Deoxyadenosines / Q000378:metabolism; D003841:Deoxycytidine / Q000378:metabolism; D003849:Deoxyguanosine / Q000378:metabolism; D003853:Deoxyribonucleosides / Q000378:metabolism*; D003857:Deoxyuridine / Q000378:metabolism; D004787:Environmental Pollution; D004811:Epichlorohydrin / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D016273:Occupational Exposure; D013936:Thymidine / Q000378:metabolism
D018736:DNA Adducts; D003839:Deoxyadenosines; D003853:Deoxyribonucleosides; D004811:Epichlorohydrin; D003841:Deoxycytidine; D003849:Deoxyguanosine; D013936:Thymidine; D003857:Deoxyuridine