Phenylalanine monooxygenase and the sulfur oxygenation of S-carboxymethyl-L-cysteine in mice

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Evita VandenbosscheGlyn B Steventon

Abstract

1. The extent of sulfoxidation of the drug, S-carboxymethyl-L-cysteine, has been shown to vary between individuals, with this phenomenon being mooted as a biomarker for certain disease states and susceptibilities. Studies in vitro have indicated that the enzyme responsible for this reaction was phenylalanine monooxygenase but to date no in vivo evidence exists to support this assumption. Using the mouse models of mild hyperphenylalaninamia (enu1 PAH variant) and classical phenylketonuria (enu2 PAH variant), the sulfur oxygenation of S-carboxymethyl-L-cysteine has been investigated. 2. Compared to the wild type (wt/wt) mice, both the heterozygous dominant (wt/enu1 and wt/enu2) mice and the homozygous recessive (enu1/enu1 and enu2/enu2) mice were shown to have significantly increased Cmax, AUC(0-180 min) and AUC(0-∞ min) values (15 - to 20-fold higher). These results were primarily attributable to the significantly reduced clearance of S-carboxymethyl-L-cysteine (13 - to 22-fold lower). 3. Only the wild type mice produced measurable quantities of the parent S-oxide metabolites. Those mice possessing one or more allelic variant showed no evidence of blood SCMC (R/S) S-oxides. These observations support the proposition that differe...Continue Reading

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Citations

Apr 13, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Glyn B Steventon, Stephen C Mitchell
Jun 25, 2019·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Stephen C Mitchell, Glyn B Steventon

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