Comparative mutagenicity of 7H-dibenzo[c,g]carbazole and two derivatives in MutaMouse liver and skin.
7H-Dibenzo[c,g]carbazole (DBC) is an environmental pollutant that produces DNA adducts and tumors in mouse liver and skin following subcutaneous injection and topical application. The two synthetic derivatives 5,9-dimethyl-DBC (DMDBC) and N7-methyl-DBC (NMDBC) induce tissue-specific lesions. DNA adducts and tumors are observed only in liver following exposure to DMDBC and only in skin following exposure to NMDBC. We used the positive selection MutaMouse model to measure the induction of mutations in the two target organs, 28 days after a single subcutaneous injection or topical application of DBC, DMDBC and NMDBC. In liver, DBC and DMDBC induced 30- to 50-fold increases in mutant frequency (MF), while NMDBC had only a weak effect, regardless of the route of administration. After topical application, DBC and NMDBC produced 3.4- to 7.9-fold increases in MF in skin, while DMDBC had a weak effect. After subcutaneous injection, the three compounds had no or weak effect in skin. This study shows gene mutations arise in the respective target organs in which primary DNA damage and tumors are observed. These results illustrate the relevance of the MutaMouse model for testing organ-specific mutagens.
Renault
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D
Rhône-Poulenc Rorer, Drug Safety Department, 13 Quai Jules Guesde, BP 14, F-94403 Vitry sur Seine, France.
Tombolan
F
F
Brault
D
D
Périn
F
F
Thybaud
V
V
D000279:Administration, Cutaneous; D000818:Animals; D002227:Carbazoles / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D007279:Injections, Subcutaneous; D007763:Lac Operon; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009154:Mutation; D012867:Skin / Q000187:drug effects*
D002227:Carbazoles; D002273:Carcinogens; C041150:N-methyl-7H-dibenzo(c,g)carbazole; C039387:5,9-dimethyldibenzo(c,g)carbazole; C013478:7H-dibenzo(c,g)carbazole