Fjord-region diol-epoxides of benzo[c]chrysene are potent inducers of micronuclei in murine bone marrow.
Vicinal diol-epoxides are the best established carcinogenic metabolites of polycyclic aromatic hydrocarbons. Numerous studies have demonstrated their high genotoxic activity in various in vitro test systems. However, in vivo mutagenicity data are not available. The fjord-region diol-epoxides of benzo[c]chrysene combine high mutagenic activity in vitro with high hydrolytic stability. They were tested for the induction of micronuclei in the bone marrow following intraperitoneal administration to NMRI mice. The anti diastereomer of the diol-epoxide enhanced the frequency of micronucleated polychromatic erythrocytes strongly (7-19-fold above the value in untreated controls) over a very wide dose range (2.5-300 mumol/kg body weight). The syn diastereomer demonstrated similar effects, but required about 5 times higher doses. The corresponding proximate mutagen, benzo[c]chrysene-trans-9,10-dihydrodiol, was only moderately active, whereas the positive control substance, benzo[a]pyrene-trans-7,8-dihydrodiol, was strongly active. The study indicates that intraperitoneally administered diol-epoxides of benzo[c]chrysene may reach the bone marrow. Therefore, it will be possible to study the influence of metabolic modulation, e.g. by enzyme induction, on the effects of these ultimate mutagens and their metabolic precursors in vivo.
Glatt
H
H
Department of Toxicology, University of Mainz, Germany.
Seidel
A
A
Oesch
F
F
Gumbsch
A
A
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002911:Chrysenes / Q000633:toxicity*; D004852:Epoxy Compounds / Q000633:toxicity*; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*
D002911:Chrysenes; D004852:Epoxy Compounds; D009153:Mutagens