Organ-specific, carcinogenic dibenzo[c,g]carbazole derivatives: discriminative response in S. typhimurium TA100 mutagenesis modulated by subcellular fractions of mouse liver.
7H-Dibenzo[c,g]carbazole (DBC) has carcinogenic effects on mouse subcutaneous fibroblasts and liver; the N-methyl derivative (N-MeDBC) induces only sarcomas; 3-methyl- and 5,9-dimethyldibenzo[c,g]carbazole (3-MeDBC and 5,9-DMeDBC) are specific, potent hepatocarcinogens in mice. The mutagenicity in S. typhimurium TA100 of these 4 compounds was evaluated in relation to the concentration of mouse liver 9000 X g supernatant (S9) and to the proportions of microsomes and cytosol in the medium. Optimal mutagenicity of N-MeDBC was seen with a low concentration of S9 or microsomes; a 5-10 times higher concentration of the subcellular fraction was necessary to induce optimal mutagenicity of the hepatocarcinogens 3-MeDBC and 5,9-DMeDBC. Intermediate quantities were needed in the case of DBC, which is carcinogenic in both cell types. Whereas the presence of cytosol had an inhibitory effect on the mutagenicity of the sarcomagenic N-MeDBC, the cytosolic fraction was essential for optimal mutagenic expression by the 2 hepatocarcinogenic derivatives. The activating cytosolic fraction is not inducible. These experiments show that programmed modulation of the metabolic activation system in the Ames test can be used to study organ-specific chemical carcinogenesis. The results suggest that differences in the enzymatic composition of target tissues are a determining factor in the organ specificity of carcinogens such as DBC.
Périn
F
F
Institut Curie, Cancérogénèse Expérimentale, Centre Universitaire, Orsay, France.
Valéro
D
D
Thybaud-Lambay
V
V
Plessis
M J
MJ
Zajdela
F
F
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests; D010634:Phenobarbital / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000187:drug effects*; D013347:Subcellular Fractions / Q000378:metabolism
D001140:Aroclors; D002227:Carbazoles; D008748:Methylcholanthrene; D010634:Phenobarbital