Evidence for the involvement of a bis-diol-epoxide in the metabolic activation of dibenz[a,h]anthracene to DNA-binding species in mouse skin.
Dibenz[a,h]anthracene (DB[a,h]A) and its microsomal metabolites, trans-3,4-dihydro-3,4-dihydroxydibenz[a,h]anthracene (DBA-3,4-diol), trans,trans-3,4:8,9-tetrahydro-3,4:8,9-tetrahydroxydibenz[a,h]anth racene, trans,trans-3,4:10,11-tetrahydro-3,4:10,11-tetrahydroxydibenz[a,h] - anthracene (DBA-3,4,10,11-bis-diol) and trans,trans-3,4:12,13-tetrahydro-3,4:12,13- tetrahydroxydibenz[a,h]anthracene were each applied topically to mouse skin and the epidermal DNA isolated 24 h later. 32P-postlabeling analysis of each of the DNA samples was performed. DNA from mice treated with DB[a,h]A produced an adduct map on TLC consisting of one major and three minor adduct spots. A similar pattern of spots was produced by DBA-3,4-diol. No detectable DNA adducts were produced by trans,trans-3,4:12,13-tetrahydro-3,4:12,13-tetrahydroxy- dibenz[a,h]anthracene, although a single, minor adduct spot was produced by trans,trans-3,4:8,9-tetrahydro-3,4:8,9-tetrahydroxydibenz[a,h]- anthracene. However, DBA-3,4,10,11-bis-diol was found to produce a major single adduct that comigrated on thin layer chromatography with the major adduct produced by both DB[a,h]A and DBA-3,4-diol. In addition, this adduct was present at a level 10 times higher than the corresponding adduct produced by treatment with the parent hydrocarbon. Coelution of the major adducts formed from DB[a,h]A and DBA-3,4-diol with that formed from DBA-3,4,10,11-bis-diol was also demonstrated on reverse-phase high performance liquid chromatography. Thus, we propose that, in mouse skin, the major pathway of DB[a,h]A activation to DNA binding products is via a 3,4-diol to the 3,4,10,11-bis-diol and ultimately to a bis-diol-epoxide (potentially the 3,4,10,11-bis-dihydrodiol-1,2-oxide).
Carmichael
P L
PL
Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, United Kingdom.
Platt
K L
KL
Shé
M N
MN
Lecoq
S
S
Oesch
F
F
Phillips
D H
DH
Grover
P L
PL
D000818:Animals; D001551:Benz(a)Anthracenes / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004247:DNA / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism*; D008297:Male; D051379:Mice; D012867:Skin / Q000378:metabolism*
D001551:Benz(a)Anthracenes; D004852:Epoxy Compounds; D004247:DNA; C026486:1,2,5,6-dibenzanthracene