title: Biochemical characterization of porphobilinogen deaminase-deficient mice during phenobarbital induction of heme synthesis and the effect of enzyme replacement.
abstract: Acute intermittent porphyria (AIP) is a genetic disorder caused by a deficiency of porphobilinogen deaminase (PBGD), the 3rd enzyme in heme synthesis. It is clinically characterized by acute attacks of neuropsychiatric symptoms and biochemically by increased urinary excretion of the porphyrin precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA). A mouse model that is partially deficient in PBGD and biochemically mimics AIP after induction of the hepatic ALA synthase by phenobarbital was used in this study to identify the site of formation of the presumably toxic porphyrin precursors and study the effect of enzyme-replacement therapy by using recombinant human PBGD (rhPBGD). After 4 d of phenobarbital administration, high levels of PBG and ALA were found in liver, kidney, plasma, and urine of the PBGD-deficient mice. The administration of rhPBGD intravenously or subcutaneously after a 4-d phenobarbital induction was shown to lower the PBG level in plasma in a dose-dependent manner with maximal effect seen after 30 min and 2 h, respectively. Injection of rhPBGD subcutaneously twice daily during a 4-d phenobarbital induction reduced urinary PBG excretion to 25% of the levels found in PBGD-deficient mice administered with only phenobarbital. This study points to the liver as the main producer of PBG and ALA in the phenobarbital-induced PBGD-deficient mice and demonstrates efficient removal of accumulated PBG in plasma and urine by enzyme-replacement therapy.
authors.affiliation: Porphyria Centre Sweden, Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden. Annika.Johansson@labmed.ki.se
authors.forename: Annika
authors.initials: A
authors.lastname: Johansson
authors.forename: Christer
authors.initials: C
authors.lastname: Möller
authors.forename: Jens
authors.initials: J
authors.lastname: Fogh
authors.forename: Pauline
authors.initials: P
authors.lastname: Harper
mesh_terms: D000622:Aminolevulinic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D000818:Animals; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005260:Female; D006418:Heme / Q000096:biosynthesis*; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010634:Phenobarbital / Q000494:pharmacology*; D011162:Porphobilinogen / Q000097:blood / Q000652:urine; D017118:Porphyria, Acute Intermittent / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D011994:Recombinant Proteins; D006418:Heme; D011162:Porphobilinogen; C058222:2-amino-5-hydroxy-4-oxopentanoic acid; D000622:Aminolevulinic Acid; D011163:Hydroxymethylbilane Synthase; D010634:Phenobarbital