Characterization of highly polar bis-dihydrodiol epoxide--DNA adducts formed after metabolic activation of dibenz[a,h]anthracene.
Dibenz[a,h]anthracene as well as a biologically important metabolite of dibenz[a,h]anthracene, namely the M-region dihydrodiol trans-3,4-dihydroxy-3,4-dihydrodibenz[a,h]anthracene were in addition to further metabolism to a bay region diol epoxide, extensively transformed to a distal bisdihydrodiol, 3,4,10,11-tetrahydroxy-3,4,10,11-tetrahydro-dibenz[a,h]anthracene, which exhibited after renewed metabolic activation high DNA binding efficiency, leading to a new class of very polar DNA adducts. After incubation of dibenz[a,h]anthracene with DNA in the presence of liver microsomes from Aroclor 1254 treated male Sprague-Dawley rats highly polar DNA adducts probably originating from 3R,4R,10R,11R-tetrahydroxy-3,4,10,11-tetrahydrodibenz[a,h]an thracene and 3R,4R,10S,11S-tetrahydroxy-3,4,10,11-tetrahydrodibenz[a,h]anthr ace ne were identified by reversed phase HPLC and by the 32P-postlabeling method. The adducts obtained were further characterized by comparing their fluorescence spectra with those obtained from 3,4,10,11-tetrahydroxy- 3,4,10,11-tetrahydrodibenz[a,h]anthracene and from 3,4-dihydroxy-3,4-dihydrodibenz[a]anthracene, the putative chromophore of the polar adduct. DNA adducts formed via 3S,4S,10S,11S-tetrahydroxy-3,4,10,11-tetrahydro- dibenz[a,h]anthracene were not found. After incubation of 14C-labelled dibenz[a,h]anthracene highly polar DNA adducts derived from the bisdihydrodiol contributed 38% to the adducts found in the HPLC profile. Bay region diol epoxide adducts represented a fraction of 25%. Using the 32P-postlabelling technique a higher DNA binding yield for the racemic bisdihydrodiol (38 +/- 12 pmol/mg DNA) was calculated than for the most active 3,4-dihydrodiol enantiomer, 3R,4R-dihydroxy-3,4- dihydrodibenz[a,h]anthracene (23 +/- 6 pmol/mg DNA).
Institute of Toxicology, University of Mainz, Germany.
J
J
Fuchs
J
J
Mlcoch
K L
KL
Platt
F
F
Oesch
D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D003853:Deoxyribonucleosides / Q000302:isolation & purification; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence
D001551:Benz(a)Anthracenes; D003853:Deoxyribonucleosides; D004247:DNA; C026486:1,2,5,6-dibenzanthracene