Reaction of nitroso derivatives of dinitropyrenes with sulfhydryl groups of peptides and hemoglobinin vitroand in rats

Abstract

Diesel engine emissions have been classified as a potential human carcinogen and may cause a variety of other health effects. Human exposure to diesel engine emissions is highly variable within the population. Therefore, specific methods for the biomonitoring of human exposure to diesel engine emissions are required for exposure assessment within epidemiological studies. Haemoglobin adducts of dinitropyrenes may serve as biomarkers for human exposures to diesel engine emissions.To characterize structures of dinitropyrene reaction products with sulfhydryl groups, glutathione was used to trap electrophilic nitroso intermediates formed from dinitropyrenes and glutathione S-conjugates were identified and characterized by Qtrap techniques using (HPLC-MS/MS) high-performance liquid chromatography coupled to triple quadrupole mass spectrometry. Nitrosonitropyrene-derived sulfinamides, sulfenamides and glutathione thioethers bound to carbon atoms in the aromatic ring, presumably formed by a rearrangement of intermediate sulfenamide cations, were formed in low yields. In haemoglobin from rats orally administered dinitropyrenes, mild alkaline hydrolysis of haemoglobin released aminonitropyrenes, which were identified by HPLC-MS/MS. The results demonstrate that dinitropyrenes undergo nitroreduction in rats and that the intermediate nitrosonitropyrenes bind to heamoglobin. The haemoglobin adducts formed from dinitropyrenes seem, in contrast to previous studies, to be hydrolysable and thus represent sulfen- and sulfinamides derived from the intermediate nitrosonitropyrenes. The developed Qtrap methods to detect and characterize glutathione S-conjugates rapidly may have wide applications in attempts to characterize reactive intermediates formed in complex mixtures in low concentrations.

Toward an “omic” physiopathology of reactive chemicals: Thirty years of mass spectrometric study of the protein adducts with endogenous and xenobiotic compounds

“…It is worth noting that not only aromatic amines, but also aromatic nitro compounds are able to yield the corresponding N-nitroso derivatives (Suzuki et al, 1989), the latter by catalysis from erythrocyte enzymes (Belisario et al, 1996). In particular, an adduct of hemoglobin with a partially reduced trinitrotoluene has been observed (Bakhtiar & Leung, 1997), while the adducts of the nitroso derivatives of the highly mutagenic environmental PAH oxidation products, dinitro-PAH, have been found to covalently bind proteins both in vitro and in exposed rats (Straube et al, 2005).…”

“…Of course, also exposure to aromatic amines of workers in fine-chemicals production plants can be monitored (Boogaard, Beulink, & Van Sittert, 1994a;Boogaard et al, 1994b). This approach is also valuable for the detection of some highly mutagenic nitrated PAH which are emitted from diesel engine exhaust (Straube et al, 2005). It is also worth noting that erythrocyte enzymes have been found able to catalyze reduction of nitro-PAH to the corresponding amino derivatives, through the intermediacy of the nitroso compounds, which have been found as covalently bound sulfinamides with hemoglobin (Belisario et al, 1996).…”

Bioactivation of Flutamide Metabolites by Human Liver Microsomes

“…group (Straube et al, 2005). Nitrosoarenes are reactive intermediates that can react with cellular thiols such as GSH and may play an important role in the biological effects of these compounds.…”