New insights into tetrahydrobiopterin pharmacodynamics from Pah, a mouse model for compound heterozygous tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency |
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Authors: | Florian B Lagler Søren W Gersting Clemens Zsifkovits Anna Eichinger Michael Staudigl Hartmut Glossmann |
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Institution: | a Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, 6020 Innsbruck, Austria b Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany c Laboratory Becker, Olgemöller, and Colleagues, 81671 Munich, Germany d Newborn Screening Laboratory, University Children's Hospital, 8032 Zurich, Switzerland |
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Abstract: | Phenylketonuria (PKU), an autosomal recessive disease with phenylalanine hydroxylase (PAH) deficiency, was recently shown to be a protein misfolding disease with loss-of-function. It can be treated by oral application of the natural PAH cofactor tetrahydrobiopterin (BH4) that acts as a pharmacological chaperone and rescues enzyme function in vivo. Here we identified Pahenu1/2 bearing a mild and a severe mutation (V106A/F363S) as a new mouse model for compound heterozygous mild PKU. Although BH4 treatment has become established in clinical routine, there is substantial lack of knowledge with regard to BH4 pharmacodynamics and the effect of the genotype on the response to treatment with the natural cofactor. To address these questions we applied an elaborate methodological setup analyzing: (i) blood phenylalanine elimination, (ii) blood phenylalanine/tyrosine ratios, and (iii) kinetics of in vivo phenylalanine oxidation using 13C-phenylalanine breath tests. We compared pharmacodynamics in wild-type, Pahenu1/1, and Pahenu1/2 mice and observed crucial differences in terms of effect size as well as effect kinetics and dose response. Results from in vivo experiments were substantiated in vitro after overexpression of wild-type, V106A, and F263S in COS-7 cells. Pharmacokinetics did not differ between Pahenu1/1 and Pahenu1/2 indicating that the differences in pharmacodynamics were not induced by divergent pharmacokinetic behavior of BH4. In conclusion, our findings show a significant impact of the genotype on the response to BH4 in PAH deficient mice. This may lead to important consequences concerning the diagnostic and therapeutic management of patients with PAH deficiency underscoring the need for individualized procedures addressing pharmacodynamic aspects. |
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Keywords: | PKU phenylketonuria PAH phenylalanine hydroxylase BH4 l-erythro-5" target="_blank">6R-l-erythro-5 6 7 8-tetrahydrobiopterin MIM Mendelian inheritance in man number EC Enzyme Commission number MHP mild hyperphenylalaninemia enu N-ethyl-N-nitrosourea BTBR black and tan brachyuric mouse strain DTT dithiothreitol Ke elimination constant c0 initial concentration cmax peak concentration tmax time to peak concentration AUC area under the concentration vs time curve at 0-180 min t1/2 elimination half-life 13C-phenylalanine l-[1-13]C-phenylalanine" target="_blank">l-[1-13]C-phenylalanine DOB delta over baseline DOBBH4 delta over baseline after BH4 treatment DOBPlacebo delta over baseline after Placebo Phe0 initial phenylalanine concentration Phe180 phenylalanine concentration at 180 min |
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