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J. Biol. Chem., Vol. 279, Issue 25, 26331-26338, June 18, 2004

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Formation of Biologically Active Oxysterols during Ozonolysis of Cholesterol Present in Lung Surfactant^*

Melissa K. Pulfer and Robert C. Murphy

From the Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80206

Exposure of the lung to concentrations of ozone found in ambient air is known to cause toxicity to the epithelial cells of the lung. Because of the chemical reactivity of ozone, it likely reacts with target molecules in pulmonary surfactant, a lipid-rich material that lines the epithelial cells in the airways. Phospholipids containing unsaturated fatty acyl groups and cholesterol would be susceptible to attack by ozone, which may lead to the formation of cytotoxic products. Whereas free radicalderived oxidized cholesterol products have been frequently studied for their cytotoxic effects, ozonized cholesterol products have not been studied, although they could reasonably play a role in the toxicity of ozone. The reaction of ozone with cholesterol yielded a complex series of products including 3-hydroxy-5-oxo-5,6-secocholestan-6-al, 5-hydroperoxy-B-homo-6-oxa-cholestan-3,7a-diol, and 5,6-epoxycholesterol. Mass spectrometry and radioactive monitoring were used to identify the major cholesterol-derived product during the reaction of 2 ppm ozone in surfactant as 5,6-epoxycholesterol, which is only a minor product during ozonolysis of cholesterol in solution. A dose-dependent formation of 5,6-epoxycholesterol was also seen during direct exposure of intact cultured human bronchial epithelial cells (16-HBE) to ozone. Studies of the metabolism of this epoxide in lung epithelial cells yielded small amounts of the expected metabolite, cholestan-3,5,6-triol, and more abundant levels of an unexpected metabolite, cholestan-6-oxo-3,5-diol. Both 5,6-epoxycholesterol and cholestan-6-oxo-3,5-diol were shown to be cytotoxic to cultured 16-HBE cells. A possible mechanism for cytotoxicity is the ability of these oxysterols to inhibit isoprenoid-based cholesterol biosynthesis in these cells.

Received for publication, March 31, 2004 , and in revised form, April 14, 2004.

^* This work was supported in part by NIEHS Grant ES012347 and National Institutes of Health Grant HL34303. 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.

To whom correspondence should be addressed: National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Tel.: 303-398-1849; Fax: 303-398-1694; E-mail: murphyr{at}njc.org.

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