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STABILITY OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF NAPHTHALENE OXIDE, 1,2-NAPHTHOQUINONE, AND 1,4-NAPHTHOQUINONE
Citation:
Troester, M. A., A B. Lindstrom, S. Waidyanatha, L. Kupper, AND S. M. Rappaport. STABILITY OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF NAPHTHALENE OXIDE, 1,2-NAPHTHOQUINONE, AND 1,4-NAPHTHOQUINONE. TOXICOLOGICAL SCIENCES 68(2):314-321, (2002).
Impact/Purpose:
The objective of this task is to develop state-of-the-art methods for measuring xenobiotic compounds, to include the isolation of the analyte from the appropriate matrix (extraction), preconcentration (typically sorbent-based), and analysis via GC/MS and/or LC/MS. Once established, these methods will be applied in small scale pilot studies or demonstration projects. Particular emphasis will be placed on methods which are readily transferable to other laboratories, including those within the Human Exposure and Atmospheric Sciences Division (HEASD), the National Exposure Research Laboratory (NERL), other EPA Laboratories, Program Offices, Regions, and academic institutions.
Specific objectives of this task include the following:
1) Development of GC/MS and LC/MS methods for the measurement of key xenobiotic compounds and their metabolites (to include the pyrethroid pesticides, perfluorinated organic compounds, and the BFRs) in relevant environmental and biological matrices.
2) Development of efficient low cost methods for the extraction and clean up of these compounds collected from relevant matrices.
3) Determination of xenobiotic compound and metabolite concentrations in samples derived from laboratory and field monitoring studies to help assess exposures and evaluate associated risks.
Description:
Naphthalene is an important industrial chemical, which has recently been shown to cause tumors of the respiratory tract in rodents. It is thought that one or more reactive metabolites of naphthalene, namely, naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ), and 1,4-naphthoquinone (1,4-NPQ) contribute to the tumorigenicity of this chemical. These electrophiles are all capable of covalent binding to macromolecules including DNA and proteins. The stability of cysteinyl adducts of NPO, 1,2-NPQ, and 1,4-NPQ were investigated in both hemoglobin (Hb) and albumin (Alb) of male F344 rats following a single administration of two different doses (400 or 800 mg naphthalene per kg body weight). To assess the stability of Alb adducts, we compared the rates of NPO-Alb turnover (half-life of approximately 2 d) and 1,2-NPQ-Alb (half-life of approximately 1 d) to the normal turnover rate of Alb in the rat (half-life = 2.5 - 3 d). Based on the rapid turnover of these adducts relative to Alb itself, we concluded that they were unstable. However, the stability of Alb adducts was not affected by the dose of naphthalene administered (400 or 800 mg/kg). In contrast, NPO-Hb adducts were relatively stable (rate constant of adduct instability<0.01) following a 400 mg/kg dose of naphthalene, but their stability could not be estimated following an 800 mg/kg dose due to high variability among animals. The rate constants of adduct instability obtained in this study allow application of NPO and NPQ adducts to estimate the exposure to reactive electrophilic metabolites of naphthalene in the rat. In addition, some limitations of current methods for estimating adduct instability were identified.
The work was supported in part by the National Institute of Environmental Health Sciences through grants P42ES05948, T32ES07018 and P30ES10126. The research described in this document was also supported in part by the U.S. Environmental Protection Agency. It has been subjected to Agency review and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.