Tumor formation in the neonatal mouse bioassay indicates that the potent carcinogen dibenzo[def,p]chrysene (dibenzo[a,l]pyrene) is activated in vivo via its trans-11,12-dihydrodiol.
The hexacyclic aromatic hydrocarbon dibenzo[def,p]chrysene, better known as dibenzo[a,l]pyrene (DBP) in the field of chemical carcinogenesis, is present in the environment as a combustion product of organic matter. This compound is probably the strongest chemical carcinogen ever tested. As ultimate genotoxic metabolites of DBP two electrophilically reactive species are discussed: (i) radical cations generated by one-electron oxidation, and (ii) fjord region dihydrodiol epoxides formed via the trans-11,12-dihydroxy 11,12-dihydro derivative of DBP (11,12-dihydrodiol). In order to delineate the metabolic pathway(s) involved in tumor formation by DBP, newborn Crl:CD-1(ICR)BR mice were intraperitoneally treated with the parent compound, its 11,12-dihydrodiol, and the two diastereomeric fjord region dihydrodiol epoxides. Due to severe acute and chronic toxicity, the total dose of DBP and of the 11,12-dihydrodiol was limited to 40 nmol. For the same reason the dihydrodiol epoxides could only be applied in doses up to 0.4 nmol. The tumor incidence was determined 55 +/- 1 weeks after treatment. Under these conditions, DBP and its 11,12-dihydrodiol induced lung tumors (incidence: 86.5% versus 92.0%; yield: 2.88 versus 7.44 tumors per mouse), liver (incidence: 57.7% versus 60.0%; yield: 3.63 versus 5.28 tumors per mouse) and other organs (incidence: 36.5% versus 32.0%; yield: 0.56 versus 0.52 tumors per mouse). By contrast, only lung tumors at low incidence were detected in mice treated with solvent only (incidence: 28.8%; yield: 0.58 tumors per mouse). As with the parent hydrocarbon, mice treated with low doses of diastereomeric syn- and anti-dihydrodiol epoxides of DBP showed increased tumor incidences in liver (incidence: 19.0 and 46.7%; yield: 0.36 and 1.47 tumors per mouse, respectively), and in various other organs (incidence: 7.1 and 20.0%; yield: 0.07 and 0.20 tumors per mouse, respectively). In consideration of the 100-fold differences in the doses of compounds applied in this study, the tumor-inducing potency increases in the order DBP < 11,12-dihydrodiol < anti-dihydrodiol epoxide. This result provides strong evidence that the potent carcinogen DBP is activated in vivo in the mouse via its 11,12-dihydrodiol and not preferentially through alternative pathways.
Platt
Karl L
KL
Institute of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131, Germany. platt@mail.uni-mainz.de
Dienes
Hans P
HP
Tommasone
Manuela
M
Luch
Andreas
A
D000818:Animals; D000831:Animals, Newborn; D001580:Benzopyrenes / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
D001580:Benzopyrenes; D002273:Carcinogens; D004101:Dihydroxydihydrobenzopyrenes; C071371:dibenzo(a,l)pyrene 11,12-dihydrodiol; C041517:dibenzo(a,l)pyrene