title: Covalent DNA adducts formed by benzo[c]chrysene in mouse epidermis and by benzo[c]chrysene fjord-region diol epoxides reacted with DNA and polynucleotides.
abstract: The metabolic activation in mouse skin of benzo[c]chrysene (B[c]C), a weakly carcinogenic polycyclic aromatic hydrocarbon (PAH) present in coal tar and crude oil, was investigated. Male Parkes mice were treated topically with 0.5 mumol of B[c]C, and DNA was isolated from the treated areas of skin at various times after treatment and analyzed by 32P-postlabeling. Seven adduct spots were detected, at a maximum level of 0.89 fmol of adducts/microgram of DNA. Four B[c]C-DNA adducts persisted in skin for at least 3 weeks. Treatment of mice with 0.5 mumol of the optically pure putative proximate carcinogens (+)- and (-)-trans-benzo[c]chrysene-9,10-dihydrodiols [(+)- and (-)-B[c]C-diols] led to the formation of adducts which comigrated on TLC and HPLC with some of those formed in B[c]C-treated mice. The major adduct formed in mouse skin treated with B[c]C coeluted on TLC and HPLC with an adduct formed in mouse skin treated with (-)-B[c]C-diol. These results suggested that the detected adducts were formed by the fjord-region B[c]C-9,10-dihydrodiol 11,12-epoxides (B[c]CDEs). To test this, the four optically pure synthetic B[c]CDEs were reacted in vitro with DNA and with synthetic polynucleotides and these samples were 32P-postlabeled. Cochromatography, both on TLC and HPLC, of in vitro and in vivo adducts indicated that B[c]C is activated in mouse skin through formation of the (-)-anti- and (+)-syn-B[c]CDE with 9R,10S,11S,12R- and 9S,10R,11S,12R- absolute configuration, respectively, both of which formed two DNA adducts in vivo. However, the major adduct present in the B[c]C-treated skin DNA was not a fjord-region B[c]CDE adduct but was possibly derived from a bay region B[c]CDE at the 1,2,3,4-position. The extent of DNA adduct formation by B[c]C in mouse skin DNA was lower than that of moderately carcinogenic PAHs previously studied by this method, suggesting a correlation between extent of DNA adduct formation and carcinogenic potential.
authors.affiliation: Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, U.K.
authors.forename: A S
authors.initials: AS
authors.lastname: Giles
authors.forename: A
authors.initials: A
authors.lastname: Seidel
authors.forename: D H
authors.initials: DH
authors.lastname: Phillips
mesh_terms: D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004247:DNA / Q000737:chemistry* / Q000302:isolation & purification; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry; D008297:Male; D051379:Mice; D010616:Phenanthrenes / Q000737:chemistry* / Q000378:metabolism; D011119:Polynucleotides / Q000737:chemistry; D015719:Single-Strand Specific DNA and RNA Endonucleases / Q000737:chemistry; D012867:Skin / Q000737:chemistry / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D018736:DNA Adducts; D004852:Epoxy Compounds; D010616:Phenanthrenes; D011119:Polynucleotides; C110144:benzo(c)chrysene; D004247:DNA; D015719:Single-Strand Specific DNA and RNA Endonucleases