天美传媒

Abstract

Humans are constantly exposed to mixtures, such as vehicle exhaust or occupational exposures, containing several thousand compounds, including many known human carcinogens. Covalent binding to DNA and formation of stable adducts is believed to be the causal link between exposure and carcinogenesis. DNA and protein adducts are well established biomarkers for the internal dose. Technical limitations, however, have prevented simultaneous and comprehensive detection of a broad spectrum of adducts. To overcome this limitation, we present here our efforts for establishing methodology suitable for comprehensive exposure assessment using the N-terminal valine adduct profile as biomarker. The method was evaluated using alkylated peptide standards and globin reacted in vitro with known alkylating agents, including butadiene mono- and di-epoxides (DEB), ethylene oxide, styrene oxide, ethylnitrosourea (ENU), propylene oxide and methyl methanesulfonate. Interestingly, ENU formed a carbamoylated adduct but none of the expected ethyl adducts. Subsequently, the method was applied to human globin samples. DEB-specific pyr-Val adducts, carbamoylated and methylated adducts were clearly detected in patients with no known exposure and represent background derived from the environment. The intra-day CV was ≤39% and inter-day CV was ≤50% for all detectable adducts. These patients were subsequently given tresulfan, a precursor to DEB, as an immunosuppressant for liver transplantation. The drug treatment caused a 2-fold increase of pyr-val adducts, demonstrating that the method can in fact determine chemical- (drug) induced adduct formation. The preliminary results suggest that the new design is suitable for human bio-monitoring of exposures to mixtures. Global exposure profiling reveal adduct profile that are distinctively different between various (I have to see which groups I will chose for that conference) exposure groups.

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