Bisdihydrodiols, rather than dihydrodiol oxides, are the principal microsomal metabolites of tumorigenic trans-3,4-dihydroxy-3,4-dihydrodibenz[a,h]anthracene

Journal Article · · Chemical Research in Toxicology; (United States)

DOI:https://doi.org/10.1021/tx00037a014· OSTI ID:6950128

Platt, K L; Schollmeier, M ^[1]

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1. Univ. of Mainz (Germany)

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 DNA with the presumed structure of a bay-region dihydrodiol oxide. Incubations of DBA-3,4-dihydrodiol (50 [mu]M) 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,t-3, c-4-tetrahydroxy-1,2,3,4-tetrahydro-DBA, while firm evidence for the presence of the diastereomeric syn-dihydrodiol were however three bisdihydrodiols: trans,trans-3,4:8,9-tetrahydroxy-3,4,8,9-tetrahydro-DBA [0.32 nmol/(nmol of P450-[center dot]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[center dot]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 wer not formed when epoxide hydrolase was inhibited (1,1,1-trichloro-2-propene oxide, 1 mM). Determination of the bacterial mutagenicity in strain TA100 of Salmonella typhimurium in the presence of a metabolic activating system revealed a stronger mutagenic effect of DBA-3,4:10,11-bisdihydrodiol (52.3 his[sup +]revertants/nmol) as compared to its metabolic precursor, DBA-3,4-dihydrodiol (34.5 his[sup +] revertants/nmol), while the two other bisidhydrodiols contribute only little to the genotoxic activity of the M-region dihydrodiol. 42 refs., 8 figs., 3 tabs.

• OSTI ID: 6950128
• Journal Information: Chemical Research in Toxicology; (United States), Journal Name: Chemical Research in Toxicology; (United States) Vol. 7:1; ISSN CRTOEC; ISSN 0893-228X
• Country of Publication: United States
• Language: English

Related Subjects

550200 -- Biochemistry
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
ANTHRACENE
AROMATICS
BACTERIA
CARCINOGENESIS
CELL TRANSFORMATIONS
CONDENSED AROMATICS
DNA
HYDROCARBONS
MAMMALS
METABOLISM
METABOLITES
MICROORGANISMS
NUCLEIC ACIDS
ONCOGENIC TRANSFORMATIONS
ORGANIC COMPOUNDS
PATHOGENESIS
PRECURSOR
RATS
RODENTS
SALMONELLA
SALMONELLA TYPHIMURIUM
VERTEBRATES