Cyclic adducts and intermediates induced by simple epoxides.
Simple epoxides such as ethylene oxide, propylene oxide, epichlorohydrin and glycidol are mutagenic and carcinogenic compounds that are important industrial chemicals. Mutagenic and carcinogenic epoxides can also be formed metabolically from Industrially important compounds such as alkenes (ethylene, butadiene, propylene and styrene), vinyl halides (vinyl chloride and vinyl bromide) and other vinyl monomers (acrylonitrile and acrylamide). Simple epoxides react with nucleosides and DNA predominantly by the SN2 mechanism at the most nucleophilic sites (ring nitrogens) in DNA to form 2-hydroxy-2-alkyl adducts. The major hydroxyalkyl adducts that form at N7 of deoxyguanosine and N3 of deoxyadenosine are chemically unstable owing to the presence of a charged quaternary nitrogen at the site of alkylation, and they depurinate spontaneously to remove the charge, forming potentially mutagenic abasic sites. Hydroxyalkylation at N1 of deoxyadenosine and N3 of deoxycytidine also results in the production of charged, unstable species because the pKa increases dramatically after alkylation. The charge can be lost from these adducts by the formation of cyclic adducts, which occurs when there is a good leaving group on the hydroxyalkyl side-chain. Most simple epoxides remove the charge on hydroxyalkyl adducts at N1 of deoxyadenosine and N3 of deoxyxytidine by competitive rearrangements, such as hydrolytic deamination, to form 1-hydroxyalkyl-deoxyinosine and 3-hydroxyalkyl-deoxyuridine adducts and Dimroth rearrangement to form N6-hydroxyalkyl-deoxyadenosine adducts. These rearrangements are facilitated intramolecularly by the formation of cyclic intermediates, with the participation of the hydroxyl group of the hydroxyalkyl side-chain. These adducts are uncharged, stable and potentially mutagenic and are likely to contribute to the biological activity of simple epoxides.
Solomon
J J
JJ
Nelson Institute of Environmental Medicine, New York University School of Medicine 10987, USA.
D000478:Alkylation; D018736:DNA Adducts / Q000096:biosynthesis* / Q000737:chemistry; D003641:Deamination; D003839:Deoxyadenosines / Q000737:chemistry / Q000378:metabolism; D003841:Deoxycytidine / Q000737:chemistry / Q000378:metabolism; D003857:Deoxyuridine / Q000737:chemistry / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008956:Models, Chemical
D018736:DNA Adducts; D003839:Deoxyadenosines; D004852:Epoxy Compounds; D003841:Deoxycytidine; D003857:Deoxyuridine