Tissue-specific activities of methylated dibenzo[c,g]carbazoles in mice: carcinogenicity, DNA adduct formation, and CYP1A induction in liver and skin.
The potent multitissue carcinogen 7H-dibenzo[c,g]carbazole and nine methylated derivatives, synthesized on the basis of the positions in the parent compound that are involved in metabolism, were tested for their ability to induce sarcomas and hepatic tumors in XVIInc/Z mice. In addition, the capacity of these compounds to induce DNA adducts in skin and liver was investigated by (32)P-postlabeling analysis after their topical administration. Induction by these compounds of cytochromes P450 of the 1A family in liver and skin was investigated and correlated to their carcinogenic potential. A clear correlation was found between the tissue specificity of DNA binding and the capacity of each compound to induce skin or liver tumors. In contrast, no direct relationship was observed between the capacity of the compounds to induce cytochromes 1A1/1A2 and the tissue specificity of carcinogenesis or DNA binding in liver or skin. The results are discussed with respect to the positions of methyl groups in the 7H-dibenzo[c,g]carbazole molecule.
Taras-Valéro
D
D
Génotoxicité et Cancérogénèse, Institut Curie, Faculté des Sciences, Orsay, France.
Périn-Roussel
O
O
Plessis
M J
MJ
Zajdela
F
F
Périn
F
F
D000818:Animals; D002227:Carbazoles / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D018736:DNA Adducts; D004790:Enzyme Induction; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008745:Methylation; D051379:Mice; D012867:Skin / Q000187:drug effects* / Q000201:enzymology
D002227:Carbazoles; D018736:DNA Adducts; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C013478:7H-dibenzo(c,g)carbazole