Diaminonaphthalenes and related aminocompounds: mutagenicity, CYP1A induction and interaction with the Ah receptor

Using 1- and 2-aminonaphthalene as model substrates, we investigated the effect of insertion of a second amino group on mutagenicity, binding to the cytosolic Ah receptor and CYP1A inducibility, and the effects were compared to those elicited by 3,3'-diaminobenzidine and 1-naphthylethylenediamine. 1,5- and 1,8-diaminonaphthalene were effective inducers of CYP1A activity, more potent than 1-aminonaphthalene. 2,3-Diaminonaphthalene was also an inducer of CYP1A, but the effect was similar to that elicited by 2-aminonaphthalene. In contrast, 3,3'-diaminobenzidine and 1-naphthylethylenediamine did not induce CYP1A activity. All aminonaphthalenes displaced [3H]TCDD from the Ah receptor, whereas 3,3'-diaminobenzidine and 1-naphthylethylenediamine failed to do so. The latter two compounds did not elicit a mutagenic response in the Ames test. Introduction of a second amino group at the 3-position of 2-aminonaphthalene did not modulate its mutagenicity. In the case of the non-mutagenic 1-aminonaphthalene, introduction of a second amino group at position 5 had no effect but when it was incorporated at position 8, mutagenic potential was conferred to the molecule. Computer modelling of the putative active site of CYP1A2 revealed that 1,5-diaminonaphthalene is orientated so that the distance of the second amino group from the iron-oxene is 4.037 A while in the case of 1,8-diaminonaphthalene the distance is shorter, 2.744 A, favouring its activation through N-hydroxylation. Of the compounds studied, 1,8-diaminonaphthalene and, to a lesser extent, 2,3-diaminonaphthalene autoinduced their activation. It is concluded that insertion of a second amino group at the 5- or 8-position of 1-aminonaphthalene may enhance biological activity but in the case of 2-aminonaphthalene insertion of a second amino group at position 3 had no major effect.