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.
Cheung
Y L
YL
Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford, UK.
Lewis
D F
DF
Ridd
T I
TI
Gray
T J
TJ
Ioannides
C
C
D015057:1-Naphthylamine / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D015100:3,3'-Diaminobenzidine / Q000633:toxicity; D000588:Amines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001667:Binding, Competitive; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D003198:Computer Simulation; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005029:Ethylenediamines / Q000737:chemistry / Q000633:toxicity; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000588:Amines; D002273:Carcinogens; D005029:Ethylenediamines; D009153:Mutagens; D009281:Naphthalenes; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C026373:2,3-diaminonaphthalene; D015100:3,3'-Diaminobenzidine; C031234:ethylenediamine; D015057:1-Naphthylamine; D015081:2-Naphthylamine; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2