Detection of the major DNA adducts of benzo[j]fluoranthene in mouse skin: nonclassical dihydrodiol epoxides.
Studies have demonstrated that the metabolic activation of benzo[j]fluoranthene (B[j]F) to a genotoxic agent proceeds through the formation of either the trans-4,5-dihydrodiol (B[j]F-4,5-diol) or the trans-9,10-dihydrodiol (B[j]F-9,10-diol) metabolite of B[j]F. Using 32P-postlabeling analysis, the profiles of DNA adducts formed in vivo in mouse skin from B[j]F-4,5-diol and B[j]F-9,10-diol were obtained to establish the contribution of each of these dihydrodiols to the formation of B[j]F-DNA adducts in vivo. B[j]F, B[j]F-4,5-diol and B[j]F-9,10-diol were applied to the shaved backs of mice (100 micrograms/mouse), and DNA adducts were isolated and separated using multidimensional TLC and reverse-phase HPLC. The greatest level of adducts was observed with B[j]F-4,5-diol, which resulted in the formation of 383 pmol of DNA adducts/mg of DNA. This level of DNA modification was more than 2 orders of magnitude greater than that observed with B[j]F or B[j]F-9,10-diol. The major adducts detected from the application of B[j]F-4,5-diol to mouse skin in vivo had chromatographic properties similar to those of the major adducts detected with B[j]F. In contrast, the major DNA adducts detected with B[j]F-9,10-diol had chromatographic properties distinctly different than the adducts formed from either B[j]F or B[j]F-4,5-diol. DNA adducts formed from the syn and anti isomers of the 4,5-dihydrodiol 6,6a-epoxide and the 9,10-dihydrodiol 11,12-epoxide of B[j]F were also evaluated. Each dihydrodiol epoxide derivative was reacted with calf thymus DNA in vitro and applied to mouse skin in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
Weyand
E H
EH
College of Pharmacy, Rutgers, State University of New Jersey, Piscataway 08855-0789.
Bryla
P
P
Wu
Y
Y
He
Z M
ZM
LaVoie
E J
EJ
D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005449:Fluorenes / Q000493:pharmacokinetics* / Q000633:toxicity; D051379:Mice; D009711:Nucleotides / Q000737:chemistry; D012867:Skin / Q000187:drug effects / Q000378:metabolism*
D002273:Carcinogens; D005449:Fluorenes; D009711:Nucleotides; C027704:benzo(j)fluoranthene; D004247:DNA