The NIH-shift in the in vivo hydroxylation of ring-deuterated L-phenylalanine in man.

Oral loading with L-[ring-2H5]phenylalanine has been performed at a dose of 25 mg/kg for detection of heterozygotes for classic phenylketonuria. Using three differently labeled batches of ring-deuterated L-phenylalanine, quantitative analysis of deuterium-labeled L-phenylalanine and L-tyrosine in plasma revealed different label distributions. Three different reaction mechanisms for the 4-hydroxylation of L-phenylalanine to L-tyrosine were used as the basis for model calculations of the transformation of the L-phenylalanine label distribution into that of L-tyrosine. The best agreement between observed and calculated distributions was found for the mechanism involving a migration of the 4-substituent into the 3- or 5-position (NIH-shift), followed by a random loss of the 4-/3- or the 4-/5-substituent from this intermediate structure.