Synthesis of anti-1,2-dihydroxy-3,4-epoxy-1,2,3, 4-tetrahydro-6-nitrochrysene and its reaction with 2'-deoxyguanosine- 5'-monophosphate, 2'-deoxyadenosine-5'-monophosphate, and calf thymus DNA in vitro.
The remarkable carcinogenic activity of 6-nitrochrysene (6-NC) in several animal models, and its environmental presence, suggest its potential importance with regard to human cancer development. Depending on the bioassay model, 6-NC can be activated by simple nitro reduction, ring oxidation, or by a combination of ring oxidation and nitro reduction. Only the first pathway has been clearly established. Thus, this study purports to unequivocally define the other pathways. Toward this end, we report for the first time the synthesis of anti-1,2-dihydroxy-3,4-epoxy-1,2,3, 4-tetrahydro-6-nitrochrysene (6-NCDE), a likely ultimate carcinogenic metabolite of 6-NC. Also, we describe our initial investigation of its binding with calf thymus DNA, 2'-deoxyguanosine-5'-monophosphate (2'-dGuo), and 2'-deoxyadenosine-5'-monophosphate (2'-dAdo) in vitro. These adduct markers were then employed for comparison with those obtained in the rat after in vivo treatment with 6-NC. On the basis of the results, it appears that the major adduct formed in the liver of rats treated with 6-NC is not derived from 6-NCDE.
Krzeminski
J
J
Organic Synthesis Facility, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595, USA.
Desai
D
D
Lin
J M
JM
Serebryany
V
V
El-Bayoumy
K
K
Amin
S
S
D000818:Animals; D002273:Carcinogens / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D002911:Chrysenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D018736:DNA Adducts / Q000096:biosynthesis; D003838:Deoxyadenine Nucleotides / Q000378:metabolism* / Q000633:toxicity; D003848:Deoxyguanine Nucleotides / Q000378:metabolism* / Q000633:toxicity; D008279:Magnetic Resonance Imaging; D013950:Thymus Gland / Q000737:chemistry / Q000378:metabolism
D002273:Carcinogens; D002911:Chrysenes; D018736:DNA Adducts; D003838:Deoxyadenine Nucleotides; D003848:Deoxyguanine Nucleotides; C418022:anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahdro-6-nitrochrysene; C012873:2'-deoxy-5'-adenosine monophosphate; C007257:2'-deoxyguanosine 5'-phosphate; C035986:6-nitrochrysene; D004247:DNA