Among aminoaromatics, 2,4-diaminotoluene (2,4-DAT) and 2,6-diaminotoluene (2,6-DAT) represent a conflicting couple of isomers; despite showing the same structural alert to DNA reactivity (and thus potential genotoxicity), they are different in terms of carcinogenicity. Of the two, 2,4-DAT alone is a potent rodent carcinogen, the liver being its major target. According to the literature, assays using various short-term genotoxicity tests have not discriminated satisfactorily between the carcinogenic and non-carcinogenic isomer, both chemicals producing overall positive results. To investigate their mechanism of action, we assayed both 2,4-DAT and 2,6-DAT in F-344 rat liver for their ability to induce DNA adducts, as detected by the P-32-postlabelling technique, and to enhance the induction of preneoplastic foci, as detected by GGT-staining in diethylnitrosamine (DENA)-initiated hepatocytes. Our expectation was that, using the correct target/metabolism, a classic genotoxicity assay and an assay detecting non-genotoxic activities could, together, reflect the different carcinogenic behaviour of the two isomers. The results indicate that, at the single equimolar dose of 250 mg/kg i.p., 2,4-DAT was able to induce similar to 6500 times more DNA adducts than 2,6-DAT; the estimated RAL values for the two isomers were 18.6 x 10(-6) and 0.29 x 10(-8), respectively. Moreover, of the two, only 2,4-DAT was able to significantly enhance the growth of DENA-initiated hepatocytes. Indeed, liver sections from rats treated with 2,4-DAT (30 daily doses of 25 mg/kg, i.g.) exhibited an average total number and area of foci of 10.53/cm(2) and 1.22 mm(2)/cm(2) vs. 4.46/cm(2) and 0.33 mm(2)/cm(2), for their respective controls. By contrast, no effect on the growth of GGT-positive foci was observed when liver sections from rats treated with 2,6-DAT (30 daily doses of 50 mg/kg, i.g.) were scored (5.54 foci per cm(2) and total area of 0.42 mm(2)/cm(2)). The results indicate that in spite of the structural alert common to the two isomers, 2,4-DAT and 2,6-DAT, only the former appears to significantly affect the carcinogenic process in the liver.
GENOTOXIC AND NONGENOTOXIC ACTIVITIES OF 2,4-DIAMINOTOLUENE AND 2,6-DIAMINOTOLUENE, AS EVALUATED IN FISCHER-344 RAT-LIVER
LEDDA, GIOVANNA MARIA;COLUMBANO, AMEDEO
1995-01-01
Abstract
Among aminoaromatics, 2,4-diaminotoluene (2,4-DAT) and 2,6-diaminotoluene (2,6-DAT) represent a conflicting couple of isomers; despite showing the same structural alert to DNA reactivity (and thus potential genotoxicity), they are different in terms of carcinogenicity. Of the two, 2,4-DAT alone is a potent rodent carcinogen, the liver being its major target. According to the literature, assays using various short-term genotoxicity tests have not discriminated satisfactorily between the carcinogenic and non-carcinogenic isomer, both chemicals producing overall positive results. To investigate their mechanism of action, we assayed both 2,4-DAT and 2,6-DAT in F-344 rat liver for their ability to induce DNA adducts, as detected by the P-32-postlabelling technique, and to enhance the induction of preneoplastic foci, as detected by GGT-staining in diethylnitrosamine (DENA)-initiated hepatocytes. Our expectation was that, using the correct target/metabolism, a classic genotoxicity assay and an assay detecting non-genotoxic activities could, together, reflect the different carcinogenic behaviour of the two isomers. The results indicate that, at the single equimolar dose of 250 mg/kg i.p., 2,4-DAT was able to induce similar to 6500 times more DNA adducts than 2,6-DAT; the estimated RAL values for the two isomers were 18.6 x 10(-6) and 0.29 x 10(-8), respectively. Moreover, of the two, only 2,4-DAT was able to significantly enhance the growth of DENA-initiated hepatocytes. Indeed, liver sections from rats treated with 2,4-DAT (30 daily doses of 25 mg/kg, i.g.) exhibited an average total number and area of foci of 10.53/cm(2) and 1.22 mm(2)/cm(2) vs. 4.46/cm(2) and 0.33 mm(2)/cm(2), for their respective controls. By contrast, no effect on the growth of GGT-positive foci was observed when liver sections from rats treated with 2,6-DAT (30 daily doses of 50 mg/kg, i.g.) were scored (5.54 foci per cm(2) and total area of 0.42 mm(2)/cm(2)). The results indicate that in spite of the structural alert common to the two isomers, 2,4-DAT and 2,6-DAT, only the former appears to significantly affect the carcinogenic process in the liver.
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