Haemoglobin adducts formed by aromatic amines in smokers: sources of inter-individual variability

Abstract

Summary In a previous study we found that aromatic amines, particularly 4-aminobiphenyl, formed haemoglobin adducts at higher concentrations in the blood of smokers compared to non-smokers. We re-analyse here data on haemoglobin adducts of 14 aromatic amines in order to ascertain if the inter-individual variability left unexplained by tobacco smoking could be attributed to differences in individual metabolic patterns. For this purpose we computed residuals from analysis of variance in order to adjust for individual smoking habits (type and amount of tobacco). Residuals were correlated within two clearly distinct groups: one formed by binuclear compounds (4-aminobiphenyl, 3-aminobiphenyl and 2-naphthylamine) and the other formed by all other (i.e. mononuclear) compounds. Within each group, highly statistically significant correlation coefficients were found, whereas compounds belonging to one group were not correlated to compounds in the other group. These results can be interpreted as a suggestion that two different metabolic pathways exist, one for binuclear and one for mononuclear arylamines, and that inter-individual differences in such pathways can explain part of inter-individual variability in adduct levels. This interpretation is consistent with recent animal experiments suggesting that there are different enzyme systems for the two classes of compounds.In a previously published paper, Bryant et al. (1988) reported that the quantity of haemoglobin adducts of 3-aminobiphenyl (3-ABP) and 4-aminobiphenyl (4-ABP) was related to the number of cigarettes smoked and, for 4-ABP, to the kind of tobacco (air-or flue-cured). However, the amount and type of tobacco smoked left unexplained a considerable proportion of inter-individual variability of haemoglobin adducts of the 14 investigated arylamines, including 3-ABP, 4-ABP and 2-naphthylaine (2-NA).4-ABP and 2-NA are well known bladder carcinogens, in both humans and experimental animals (IARC, 1987). Of the 14 investigated arylamines, three were binuclear: 3-ABP and 4-ABP are formed by two benzene rings and 2-NA is a naphthalene derivative; all the others have a single aromatic ring.Here we re-analyse the same data set in order to ascertain whether the unexplained residual variability might be related to differences in individual metabolic patterns. If individual metabolic differences were responsible for part of the so far unexplained inter-individual variability in haemoglobin adducts and if chemically similar substances had, at least in part, common metabolic pathways, then one would expect the concentrations of adducts of similar amines to be correlated in the same individual, after allowing for amount and type of tobacco smoked. In other words, if the hypothesis is correct, after allowing for smoking habits, subjects showing high levels of 4-ABP adducts should also have high levels of 3-ABP adducts and subjects showing low levels of 4-ABP should also have low levels of 3-ABP. Materials and methodsSubjects and materials included in the present analysis are th...

Haemoglobin adducts from aromatic amines in children in relation to area of residence and exposure to environmental tobacco smoke

“…We still have no explanation for this paradoxical result. In smokers, these adducts are consistently elevated (Branner et al 1998;Ronco et al 1990) in accordance with the well-documented occurrence of toluidines in tobacco smoke (Grimmer and Schneider, 1995;Luceri et al 1993;Patrianakos and Homann 1979). However, the dierences in Hb adducts from toluidines between smokers and nonsmokers were much less than those from 4-ABP.…”

Hemoglobin Adducts and Urinary Metabolites of Arylamines and Nitroarenes

“…Levels of the 4ABP-Hb were lower in smokers ( n = 31) of blond tobacco (flue-cured) than in smokers ( n = 16) of black tobacco (air-cured). Fast acetylators (NAT2) had lower levels of 4ABP-Hb than slow acetylators when comparing for the same type and quantity of cigarettes smoked. − The same effect was seen for 4ABP-Hb measured by Dallinga et al in 55 smokers.…”

“…Hb-adducts of 4ABP in humans were compared with the dose (nonsmokers and smokers of blond and black tobacco). − The finding of 4ABP adducts in all nonsmokers reflects ubiquitous contamination of water, air, or food. In collaborations with other research groups, phase I (P4501A2), phase II enzymes (GST, NAT2), DNA-adduct levels in urothelial epithelial cells, smoker status, and disease outcome (bladder cancer) were compared to the Hb-adduct levels of 4ABP. ,− The working hypotheses were slow NAT2 acetylators, fast P4501A2 oxidizer, and that people with inactive GSTM1 have higher adduct levels than fast NAT2 acetylators, slow oxidizers, and people with an active GSTM1.…”

New Syntheses of DNA Adducts from Methylated Anilines Present in Tobacco Smoke

“…These compounds, along with other primary aromatic amines present in microgram quantities, may account for the positive correlation between cigarette smoking and the incidence of bladder cancer in humans (6). In this context, hemoglobin-arylamine adducts, which have been used as biomarkers of exposure, are often found at higher concentrations in the blood of smokers, compared to those in the blood of nonsmokers (13,14). 2,6-Dimethylaniline-hemoglobin adducts were also found in humans following administration of the potent anesthetic and antiarrythmic drug lidocaine (15).…”