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J. Biol. Chem., Vol. 283, Issue 25, 17131-17138, June 20, 2008

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Mercapturic Acid Conjugates of 4-Hydroxy-2-nonenal and 4-Oxo-2-nonenal Metabolites Are in Vivo Markers of Oxidative Stress^*

From the Department of Pharmaceutical Sciences and the Linus Pauling Institute, Oregon State University, Corvallis Oregon 97331

Oxidative stress-induced lipid peroxidation leads to the formation of cytotoxic and genotoxic 2-alkenals, such as 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE). Lipid-derived reactive aldehydes are subject to phase-2 metabolism and are predominantly found as mercapturic acid (MA) conjugates in urine. This study shows evidence for the in vivo formation of ONE and its phase-1 metabolites, 4-oxo-2-nonen-1-ol (ONO) and 4-oxo-2-nonenoic acid (ONA). We have detected the MA conjugates of HNE, 1,4-dihydroxy-2-nonene (DHN), 4-hydroxy-2-nonenoic acid (HNA), the lactone of HNA, ONE, ONO, and ONA in rat urine by liquid chromatography-tandem mass spectrometry comparison with synthetic standards prepared in our laboratory. CCl₄ treatment of rats, a widely accepted animal model of acute oxidative stress, resulted in a significant increase in the urinary levels of DHN-MA, HNA-MA lactone, ONE-MA, and ONA-MA. Our data suggest that conjugates of HNE and ONE metabolites have value as markers of in vivo oxidative stress and lipid peroxidation.

Received for publication, April 11, 2008 , and in revised form, April 25, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01HL081721, S10RR022589, and P30ES000210. This work was also supported by the Medical Research Foundation of Oregon. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: OR State University, 203 Pharmacy Bldg., 1601 SW Jefferson, Corvallis, OR 97331-3507. Fax: 541-737-3999; E-mail: fred.stevens{at}oregonstate.edu.

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