Fluorine probes for investigating the mechanism of activation of indeno[1,2,3-cd]pyrene to a tumorigenic agent.
Indeno[1,2,3-cd]pyrene (IP) is a non-alternant polycyclic aromatic hydrocarbon that has tumor-initiating activity on mouse skin and is carcinogenic in newborn mice and in rat lungs. Previous studies have shown that 8- and 9-hydroxyIP and IP-1,2-diol are major metabolites formed in vivo in mouse skin. 8-HydroxyIP-1,2-diol and 9-hydroxyIP-1,2-diol are also observed as in vivo metabolites of IP. Although 8-hydroxyIP had marginal tumor-initiating activity on mouse skin, IP-1,2-diol and its epoxide precursor, IP-1,2-oxide, had similar tumorigenic activity as IP. In the present study fluorine probes have been employed to investigate the contribution of metabolic activation at the 1,2 and 7-10 positions of IP. At a total initiating dose of 4.0 mumol, 2-fluoroIP induced skin tumors in 76% of the treated animals with an average of 3.9 tumors/mouse. At the same dose, IP induced a 72% incidence of tumor-bearing mice with 2.1 tumors/mouse. In contrast, 8,9-difluoroIP elicited a tumorigenic response in 40% of the treated animals with 0.6 tumors/animal. Five mice from each experimental group were killed at the conclusion of the initiation phase of the bioassay and DNA was isolated from the treated areas of skin. 32P-Postlabeling analysis of the hydrolyzed DNA indicated that IP forms one major detectable DNA adduct that migrates close to the origin. This adduct is absent in mice treated with 8,9-difluoroIP. In contrast, 2-fluoroIP forms one major adduct spot with different retention behavior as compared with the adduct formed from IP. DNA from mice treated topically with IP-1,2-diol and IP-1,2-oxide was subjected to 32P-postlabeling analysis. IP-1,2-diol forms one major DNA adduct spot with mobility similar to that observed for the IP-DNA adduct. IP-1,2-oxide displayed an intense pattern of DNA adducts centered around the location of the IP-DNA adduct. No adducts were detected which had mobility similar to that formed from 2-fluoroIP. These results are consistent with IP undergoing metabolic activation at positions 7-10 either alone or in conjunction with dihydrodiol formation at the 1,2 position.
Rice
J E
JE
Department of Pharmaceutical Chemistry, College of Pharmacy, Rutgers-The State University of New Jersey, Piscataway 08855.
Weyand
E H
EH
Burrill
C
C
LaVoie
E J
EJ
D000818:Animals; D015197:Carcinogenicity Tests; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005461:Fluorine; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D011721:Pyrenes / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced*; D013755:Tetradecanoylphorbol Acetate
D004273:DNA, Neoplasm; D011721:Pyrenes; D005461:Fluorine; D013755:Tetradecanoylphorbol Acetate; C041508:indeno(1,2,3-cd)pyrene