Bisdihydrodiols, rather than dihydrodiol oxides, are the principal microsomal metabolites of tumorigenic trans-3,4-dihydroxy-3,4-dihydrodibenz[a,h]anthracene.
Several studies on metabolism and biological activity of tumorigenic dibenz[a,h]anthracene (DBA) and its derivatives have led to the conclusion that the M-region dihydrodiol, trans-3,4-dihydroxy-3,4-dihydro-DBA (DBA-3,4-dihydrodiol), is the precursor of the ultimate mutagenic and tumorigenic metabolite of DBA with the presumed structure of a bay-region dihydrodiol oxide. Incubations of DBA-3,4-dihydrodiol (50 microM) with the microsomal hepatic fraction of Sprague-Dawley rats pretreated with Aroclor 1254 yielded more than 13 metabolites upon separation by HPLC. anti-3,4-Dihydroxy-1,2-epoxy-1,2,3,4-tetrahydro-DBA [0.27 nmol/(nmol of P450.15 min)] could be identified for the first time by UV spectroscopy, by cochromatography with the synthetic reference compound, and by its nonenzymatic hydrolysis to r-1,t-2,t-3,c-4-tetrahydroxy-1,2,3,4-tetrahydro-DBA, while firm evidence for the presence of the diastereomeric syn-dihydrodiol oxide was not obtained. Major microsomal metabolites of the M-region dihydrodiol were however three bisdihydrodiols: trans,trans-3,4:8,9-tetrahydroxy-3,4,8,9-tetrahydro-DBA [0.32 nmol/(nmol of P450.15 min)], trans,trans-3,4:10,11-tetrahydroxy-3,4,-10,11-tetrahydro-DBA [DBA-3,4:10,11-bisdihydrodiol; 1.44 nmol/(nmol of P450.15 min)], and trans,trans-3,4:12,13-tetrahydroxy-3,4,12,13-tetrahydro-DBA [0.70 nmol/(nmol of P450.15 min)], whose structures were verified by UV and mass spectrometry as well as cochromatography with synthetic reference compounds and by the observation that they were not formed when epoxide hydrolase was inhibited (1,1,1-trichloro-2-propene oxide, 1 mM).(ABSTRACT TRUNCATED AT 250 WORDS)
Platt
K L
KL
Institute of Toxicology, University of Mainz, Germany.
Schollmeier
M
M
D000818:Animals; D001551:Benz(a)Anthracenes / Q000737:chemistry / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008961:Models, Structural; D009152:Mutagenicity Tests; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D001551:Benz(a)Anthracenes; C018912:dibenzoanthracene-3,4-dihydrodiol