Hemoglobin binding of aromatic amines: molecular dosimetry and quantitative structure-activity relationships for N-oxidation.
Aromatic amines are important intermediates in industrial manufacturing. N-Oxidation to N-hydroxyarylamines is a key step in determining the genotoxic properties of aromatic amines. N-Hydroxyarylamines can form adducts with DNA, with tissue proteins, and with the blood proteins albumin and hemoglobin in a dose-dependent manner. The determination of hemoglobin adducts is a useful tool for biomonitoring exposed populations. We have established the hemoglobin binding index (HBI) [(mmole compound/mole hemoglobin)/(mmole compound/kg body weight)] of several aromatic amines in female Wistar rats. Including the values from other researchers obtained in the same rat strain, the logarithm of hemoglobin binding (logHBI) was plotted against the following parameters: the sum of the Hammett constants(sigma sigma = sigma p + sigma m), pKa, logP (octanol/water), the half-wave oxidation potential (E1/2), and the electronic descriptors of the amines and their corresponding nitrenium ions obtained by semi-empirical calculations (MNDO, AMI, and PM3), such as atomic charge densities, energies of the highest occupied molecular orbit and lowest occupied molecular orbit and their coefficients, the bond order of C-N, the dipole moments, and the reaction enthalpy [MNDOHF, AM1HF or PM3HF = Hf(nitrenium) - Hf(amine)]. The correlation coefficients were determined from the plots of all parameters against log HBI for all amines by means of linear regression analysis. The amines were classified in three groups: group 1, all parasubstituted amines (maximum, n = 9); group 2, all amines with halogens (maximun, n = 11); and group 3, all amines with alkyl groups (maximum, n = 13).(ABSTRACT TRUNCATED AT 250 WORDS)
Sabbioni
G
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Institute of Toxicology, University of Würzburg, Germany.
D000588:Amines / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005260:Female; D006454:Hemoglobins / Q000187:drug effects* / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000588:Amines; D006454:Hemoglobins