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The present study was undertaken in order to determine whether 18O-labeled sterols could be used in place of 14C-sterols in clinical studies of cholesterol metabolism. (3 beta-18OH)Cholesterol and (3 beta-18OH)sitosterol were simply and inexpensively synthesized and precisely and accurately quantified by gas chromatography/mass spectrometry. 18O-Sterols added to fecal homogenate and saponified were completely recovered. However, in a series of validation studies in humans, the fecal recoveries of orally administered (18O)cholesterol and (18O)sitosterol were significantly lower than the recoveries of 14C-sterols given simultaneously. We found that the losses were largely limited to the coprostanol and ethylcoprostanol fecal metabolites. In vitro fecal incubations of 18O-sterols and unlabeled water or of unlabeled sterols with H2(18)O indicated that the losses occurred during fecal bacterial metabolism and were likely due to 3 beta-oxygen exchange with the oxygen of water, possibly via a 3-ketosteroid intermediate. These data indicate that (18O)cholesterol and (18O)sitosterol are invalid tracers for the measurement of human cholesterol metabolism by methods based on fecal sterol recovery.

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