Biomonitoring of aromatic amines V: acetylation and deacetylation in the metabolic activation of aromatic amines as determined by haemoglobin binding.
Aromatic amines are metabolically activated by N-oxidation of either the amine or the acetamide as a first step and esterification of the resulting N-hydroxyl derivatives as a second step. Both pathways may lead to DNA-adducts and subsequently to DNA lesions and mutations. Since the accumulation of non-acetylated adducts has been associated with tumour initiating properties, the balance between acetylation and deacetylation may greatly influence the biological effect. Hydrolysable haemoglobin adducts representing the bioavailability of N-hydroxylamines and the corresponding nitroso-derivatives were analysed following oral administration to female Wistar rats of two arylamine-acetamide couples: 4-aminobiphenyl and 2-aminofluorene, and two arylamine-acetamide-diacetamide triples: benzidine and 3,3'-dichlorobenzidine. The results show that the monoacetamides are readily deacetylated in vivo whereas the diacetamides are not. A dynamic equilibrium is indicated to exist between acetylation and deacetylation, which depends on substrate specificity, and the role of deacetylation is emphasised. In addition, acetylation polymorphism was studied with 4-chloroaniline and 3,3'-dichlorobenzidine in slow acetylating A/J and rapid acetylating C57BL/6J mice. The slow acetylator genotype was associated with significantly higher haemoglobin-adduct levels for both arylamines. The results provide additional support for the use of haemoglobin adducts in biomonitoring as a dosimeter for the biologically active dose of arylamines/arylacetamides. Moreover, biomonitoring of haemoglobin adducts may provide information about an individual's susceptibility to the toxic and carcinogenic effects of these chemicals.
Department of Toxicology, University of Würzburg, Germany.
I
I
Zwirner-Baier
H G
HG
Neumann
D000107:Acetylation; D000588:Amines / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003640:Dealkylation; D004784:Environmental Monitoring; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011110:Polymorphism, Genetic; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
D000588:Amines; D001798:Blood Proteins; D006454:Hemoglobins