title: Low therapeutic threshold for hepatocyte replacement in murine phenylketonuria.
abstract: Phenylalanine homeostasis in mammals is primarily controlled by liver phenylalanine hydroxylase (PAH) activity. Inherited PAH deficiency (phenylketonuria or PKU) leads to hyperphenylalaninemia in both mice and humans. A low level of residual liver PAH activity ensures near-normal dietary protein tolerance with normal serum phenylalanine level, but the precise threshold for normal phenylalanine clearance is unknown. We employed hepatocyte transplantation under selective growth conditions to investigate the minimal number of PAH-expressing hepatocytes necessary to prevent hyperphenylalaninemia in mice. Serum phenylalanine levels remained normal in mice exhibiting nearly complete liver repopulation with PAH-deficient hepatocytes (<5% residual wild-type liver PAH activity). Conversely, transplantation of PAH-positive hepatocytes into PAH-deficient Pah(enu2) mice, a model of human PKU, yielded a significant decrease in serum phenylalanine (<700 muM) when liver repopulation exceeded approximately 5%. These data suggest that restoration of phenylalanine homeostasis requires PAH activity in only a minority of hepatocytes.
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamman
authors.forename: Heather
authors.initials: H
authors.lastname: Clark
authors.forename: Eugenio
authors.initials: E
authors.lastname: Montini
authors.forename: Muhsen
authors.initials: M
authors.lastname: Al-Dhalimy
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
authors.forename: Milton
authors.initials: M
authors.lastname: Finegold
authors.forename: Cary O
authors.initials: CO
authors.lastname: Harding
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism / Q000637:transplantation*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D010649:Phenylalanine / Q000097:blood*; D010651:Phenylalanine Hydroxylase / Q000172:deficiency / Q000378:metabolism*; D010661:Phenylketonurias / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase