G. Sabbioni, HEMOGLOBIN BINDING OF AROMATIC-AMINES - MOLECULAR DOSIMETRY AND QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS FOR N-OXIDATION, Environmental health perspectives, 99, 1993, pp. 213-216
Aromatic amines are important intermediates in industrial manufacturin
g. 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 a
lbumin and hemoglobin in a dose-dependent manner. The determination of
hemoglobin adducts is a useful tool for biomonitoring exposed populat
ions. We have established the hemoglobin binding index (HBI) [(mmole c
ompound/mole hemoglobin)/(mmole compound/kg body weight)] of several a
romatic amines in female Wistar rats. Including the values from other
researchers obtained in the same rat strain, the logarithm of hemoglob
in binding (logHBI) was plotted against the following parameters: the
sum of the Hammett constants (SIGMAsigma = sigma(p) + sigma(m)), pK(a)
, logP (octanol/water), the half-wave oxidation potential (E1/2), and
the electronic descripton of the amines and their corresponding nitren
ium ions obtained by semi-empirical calculations (MNDO, AM1, and PM3),
such as atomic charge densities, energies of the highest occupied mol
ecular orbit and lowest occupied molecular orbit and their coefficient
s, the bond order of C-N, the dipole moments, and the reaction enthalp
y [MNDOHF, AM1HF or PM3HF = Hf(nitrenium) - Hf(amine)]. The correlatio
n coefficients were determined from the plots of all parameters agains
t log HBI for all amines by means of linear regression analysis. The a
mines were classified in three groups: group 1, all para-substituted a
mines (maximum, n = 9); group 2, all amines with halogens (maximum, n
= 11), and group 3, all amines with alkyl groups (maximum, n = 13). Fo
r the amines of group 1, logHBI correlates with SIGMAsigma, AM1HF, E1/
2, the pK(a), and the logP with r = 0.84,0.73,0.72, -0.69 and 0.50, re
spectively. For the amines of group 2, logHBI correlates with pK(a), S
IGMAsigma, MNDOHF, E1/2, and logP with r = 0.81, -0.80, -0.55, -0.46,
and -0.20, respectively. For the amines of group 3, logHBI correlates
with with E1/2, PM3HF, SIGMAs, pK(a), and logP with r = 0.92, 0.89,0.7
5,0.19 and 0. 12, respectively. This investigation shows for a large v
ariety of aromatic amines the bioavailability of N-hydroxyarylamine (t
he genotoxic metabolite) and the utility of electronic descriptors for
prediction of N-oxidation.