title: Characterization of 4,4'-methylenebis(2-chloroaniline)--DNA adducts formed in vivo and in vitro.
abstract: 4,4'-Methylenebis(2-chloroaniline) (MOCA) is a genotoxic and carcinogenic industrial chemical to which there is considerable potential human exposure. Since metabolic activation and formation of DNA adducts are believed to be important for the induction of these effects, DNA was treated in vitro with radiolabeled N-hydroxy-MOCA, the presumed proximate carcinogenic metabolite formed in vivo. Two major radioactive peaks were observed after HPLC separation of enzymatic hydrolysates. The two products were analyzed by MS and characterized as N-(deoxyadenosine-8-yl)-4-amino-3-chlorobenzyl alcohol and N-(deoxyadenosin-8-yl)-4-amino-3-chlorotoluene. The same adducts were also the major adducts formed in DNA of tissues from rats treated with radiolabeled MOCA. They were eliminated from rat liver with non-linear kinetics, in agreement with observations made for other carcinogens. The selective reaction of N-hydroxy-MOCA with DNA-adenine and the formation of single arylamine ring adducts suggest a substitution mechanism involving an intermediate with strong SN1 character, aided by the negative inductive effect of the ortho-chlorine. Due to tautomer formation, the initial adduct may be inherently unstable and undergo cleavage at the 1'-carbon-methylene bond to yield the observed adducts.
authors.affiliation: National Center for Toxicological Research, Jefferson, AR 72079.
authors.forename: D
authors.initials: D
authors.lastname: Segerbäck
authors.forename: F F
authors.initials: FF
authors.lastname: Kadlubar
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008753:Methylenebis(chloroaniline) / Q000633:toxicity*; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013056:Spectrophotometry, Ultraviolet
chemical_list: D009153:Mutagens; D008753:Methylenebis(chloroaniline); D004247:DNA