REACTION OF EPICHLOROHYDRIN WITH 2'-DEOXYNUCLEOSIDES - CHARACTERIZATION OF ADDUCTS

Epichlorohydrin (ECH) is a simple 3-carbon epoxide of industrial impor tance 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 yiel ded 7-(3-chloro-2-hydroxypropyl) guanine (7-CHP-Gua) resulting from al kylation at N-7 of 2'-deoxyguanosine followed by depurination. Two unu sual adducts were also partially characterized which resulted from fur ther reaction of 7-CHP-Gua with another molecule of ECH to yield 1,7-b is(3-chloro-2-hydroxypropyl)guanine (1,7-bis-CHP-Gua) which could then cyclize with the exocyclic amino group to yield N-2-(2-hydroxypropano )-7-(3-chloro-2-hyroxypropyl) guanine (1,N-2-HP-7-CHP-Gua). Reaction w ith 2'-deoxyadenosine gave only one product, namely 1,N-6-(2-hydroxypr opano)-2'-deoxyadenosine (1,N-6-HP-dAdo). The reaction of 2'-deoxythym idine with ECH also yielded one product which was identified as 3-(3-c hloro-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 r esulted from the deamination of an initially formed 3-(3-chloro-2-hydr oxypropyl)-2'-deoxycytidine (3-CHP-dCyd), a phenomenon which we have p reviously reported to occur during the reaction of 2'-deoxycytidine wi th other aliphatic epoxides. Evidence is also presented that 3-CHP-dUr d is converted to 3-(2,3-dihydroxypropyl)-2'-deoxyuridine (3-DHP-dUrd) under physiological conditions, with a half-life of 213 h. Reaction o f 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).