Hemoglobin binding of bicyclic aromatic amines.
Aromatic diamino compounds, e.g., 4,4'-methylenebis(2-chloroaniline) (MOCA) and 4,4'-methylenedianiline (MDA), are used as curing agents in the production of elastomers. Since MOCA and MDA are mutagenic and carcinogenic, substitutes are of great commercial interest. For benzidine it has been shown that ortho substitution with methyl groups yields the nonmutagenic 3,3',5,5'-tetramethylbenzidine. Therefore, MDA analogues with large substituents in the ortho position have been synthesized. The substituents are supposed to inhibit the formation of the N-hydroxyarylamines which are the putative genotoxic intermediates. We investigated the biological availability of the N-hydroxylamines of ortho-substituted diamines and of known carcinogenic diamines in female Wistar rats, by determining hemoglobin (Hb) adducts. Hb from rats dosed with 0.5 mmol/kg diamine and from controls was isolated and hydrolyzed in base. The released diamine and monoacetyldiamine were quantified by HPLC with electrochemical detection and/or GC/MS. MDA, 4,4'-oxydianiline (ODA), 4,4'-ethylenedianiline, and 4,4'-thiodianiline (TDA) bound to hemoglobin as diamine and as monoacetyl-diamine. 4,4'-Methylenebis(2,6-dimethylaniline), 4,4'-methylenebis(2,6-diethylaniline), MOCA, and 4,4'-sulfonyldianiline (dapsone) bound only as diamine to Hb. 4,4'-Methylenebis(2,6-dichloroaniline) did not bind to Hb. Thus, the presence of two substituents in the ortho position and the presence of electron-withdrawing groups in the para position to the amino group drastically reduced the formation of Hb adducts. The amount of hemoglobin adducts was compared to their carcinogenic potency. The extent of hemoglobin binding of the bicyclic diamines (dapsone, 3,3'-dichlorobenzidine, MDA, MOCA, TDA, ODA, and benzidine) increases with their carcinogenic potency.
Sabbioni
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Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Nussbaumstrasse 26, D-80336 München, Germany. Gabriele.Sabbioni@lrz.uni-muenchen.de
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D000588:Amines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D003622:Dapsone / Q000737:chemistry; D004563:Electrochemistry; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D000588:Amines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006454:Hemoglobins; D009153:Mutagens; D003622:Dapsone