title: ortho-Substituent effects on the in vitro and in vivo genotoxicity of benzidine derivatives.
abstract: Benzidine and its 3,3'-diamino, 3,3'-dimethyl, 3,3'-dimethoxy, 3,3'-difluoro, 3,3'-dichloro, 3,3'-dibromo, 3,3'-dicarbomethoxy and 3,3'-dinitro derivatives together with 2-nitrobenzidine and 3-nitrobenzidine were compared for their in vitro and in vivo genotoxicity. Relative mutagenicity was established with Salmonella strains TA98, TA98/1,8-DNP6 and TA100 with and without S9 activation. All the derivatives in the presence of S9 were more mutagenic than benzidine with 3,3'-dinitro- and 3-nitro-benzidine having the greatest mutagenicity. Mutagenicity in all 3 strains with S9 activation could be correlated to electron-withdrawing ability of substituent groups, as measured by the basicity of the amines. This correlation was explained on the basis that electron-withdrawing groups could favor the stability of the mutagenic intermediate N-hydroxylamine and also enhance the reactivity of the ultimate mutagenic species, the nitrenium ion. Mutagenicity was also correlated to the energy of the lowest unoccupied molecular orbitals (ELUMO). Hydrophobicity was found to have very limited effect on the relative mutagenicity of our benzidine derivatives. The in vivo endpoint was chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of benzidine and its derivatives. In contrast to the in vitro results, while all the amines were genotoxic in vivo, only the 3-nitro derivative had a significant increase in toxicity over benzidine.
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
authors.forename: Z
authors.initials: Z
authors.lastname: You
authors.forename: M D
authors.initials: MD
authors.lastname: Brezzell
authors.forename: S K
authors.initials: SK
authors.lastname: Das
authors.forename: M C
authors.initials: MC
authors.lastname: Espadas-Torre
authors.forename: B H
authors.initials: BH
authors.lastname: Hooberman
authors.forename: J E
authors.initials: JE
authors.lastname: Sinsheimer
mesh_terms: D015100:3,3'-Diaminobenzidine / Q000633:toxicity; D015101:3,3'-Dichlorobenzidine / Q000633:toxicity; D000818:Animals; D001560:Benzidines / Q000737:chemistry* / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002869:Chromosome Aberrations; D003962:Dianisidine / Q000633:toxicity; D004735:Energy Transfer; D008110:Liver Extracts; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009574:Nitro Compounds / Q000633:toxicity; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D001560:Benzidines; D008110:Liver Extracts; D009153:Mutagens; D009574:Nitro Compounds; D015101:3,3'-Dichlorobenzidine; D015100:3,3'-Diaminobenzidine; C027665:3-methoxybenzidine; C049586:3,3'-dibromobenzidine; C049588:3,3'-difluorobenzidine; C009501:2-tolidine; D003962:Dianisidine