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In Vivo Metabolism of L-Methionine in Mice: Evidence for Stereoselective Formation of Methionine-d-Sulfoxide and Quantitation of Other Major Metabolites

Department of Comparative Biosciences, and Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin

Flavin-containing monooxygenases (FMOs) 1–4 oxidize methionine (Met) to methionine sulfoxide (MetO). FMO3, the primary isoform expressed in adult human liver, has the lowest K_m and favors methionine-d-sulfoxide (Met-d-O) formation over methionine-l-sulfoxide. Because female mice, but not males, also express FMO3 in liver, levels of Met and its major metabolites were determined in male or female mice dosed with 400 mg/kg Met i.p. The results show that Met levels in male and female mouse liver or plasma increased significantly at both 15 and 30 min after the Met treatment; Met plasma and liver levels at 30 min were similar to or lower than the corresponding levels at 15 min. Liver and plasma MetO levels increased significantly in both sexes at 30 min, and Met-d-O was the major MetO diastereomer detected. Interestingly, less than 0.1% of the Met dose was excreted in the urine (0–24 h) as Met and Met-d-O. S-Adenosylmethionine (SAM) was the major metabolite detected in liver at 15 min. Liver SAM levels at 30 min were lower than the levels at 15 min, and the plasma SAM levels at both 15 and 30 min were much lower than the corresponding levels in the liver. Increases in liver and/or plasma S-adenosyl-L-homocysteine, 5'-deoxy-5'-(methylthio)adenosine, and N-acetyl-L-methionine were also detected. Taken together, these results suggest that mice extensively and rapidly used the Met dose. Although mice exhibited increases in tissue MetO levels, a major role for FMO3 in Met-d-O formation is not certain since the MetO increases were mostly similar in both males and females.

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				J. T. Dever and A. A. Elfarra L-Methionine Toxicity in Freshly Isolated Mouse Hepatocytes Is Gender-Dependent and Mediated in Part by Transamination J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 809 - 817. [Abstract] [Full Text] [PDF]