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Dose-Response Relationships for N7-(2-Hydroxyethyl)Guanine Induced by Low-Dose [¹⁴C]Ethylene Oxide: Evidence for a Novel Mechanism of Endogenous Adduct Formation

¹ Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom; ² Lawrence Livermore National Laboratory, Livermore, California; and ³ Swansea University, Swansea, United Kingdom

Requests for reprints: Karen Brown, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7LX, United Kingdom. Phone: 44-116-223-1851; Fax: 44-116-223-1855; E-mail: kb20{at}le.ac.uk.

Key Words: adduct • dose response • ethylene oxide

Ethylene oxide (EO) is widely used in the chemical industry and is also formed in humans through the metabolic oxidation of ethylene, generated during physiologic processes. EO is classified as a human carcinogen and is a direct acting alkylating agent, primarily forming N7-(2-hydroxyethyl)guanine (N7-HEG). To conduct accurate human risk assessments, it is vital to ascertain the relative contribution of endogenously versus exogenously derived DNA damage and identify the sources of background lesions. We have therefore defined in vivo dose-response relationships over a concentration range relevant to human EO exposures using a dual-isotope approach. By combining liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography-accelerator mass spectrometry analysis, both the endogenous and exogenous N7-HEG adducts were quantified in tissues of [¹⁴C]EO-treated rats. Levels of [¹⁴C]N7-HEG induced in spleen, liver, and stomach DNA increased in a linear manner from 0.002 to 4 adducts/10⁸ nucleotides. More importantly, the extent of damage arising through this route was insignificant compared with the background abundance of N7-HEG naturally present. However, at the two highest doses, [¹⁴C]EO exposure caused a significant increase in endogenous N7-HEG formation in liver and spleen, suggesting that EO can induce physiologic pathways responsible for ethylene generation in vivo and thereby indirectly promote N7-HEG production. We present evidence for a novel mechanism of adduct formation to explain this phenomenon, involving oxidative stress and 1-aminocyclopropane-1-carboxylic acid as a potential biosynthetic precursor to ethylene in mammalian cells. Based on the proposed pathway, N7-HEG may have potential as a biomarker of cellular oxidative stress. [Cancer Res 2009;69(7):3052–9]