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Xenobiotica
the fate of foreign compounds in biological systems
Volume 46, 2016 - Issue 4
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Pharmacogenetics

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

, , , , &
Pages 379-384 | Received 12 Jun 2015, Accepted 19 Jul 2015, Published online: 17 Aug 2015
 

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 differences in phenylalanine hydroxylase activity underlie the variation in S-carboxymethyl-l-cysteine sulfoxidation and that no other enzyme is able to undertake this reaction.

Declaration of interest

None of the authors have received any financial support from any organization involved in the production or marketing of S-carboxymethyl-l-cysteine. The authors alone are responsible for the construction of this manuscript.

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