title: Hepatocyte transplantation ameliorates the metabolic abnormality in a mouse model of acute intermittent porphyria.
abstract: Acute intermittent porphyria (AIP) is an autosomal dominant disorder characterized by insufficient porphobilinogen deaminase (PBGD) activity. When hepatic heme synthesis is induced, porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) accumulate, which causes clinical symptoms such as abdominal pain, neuropathy, and psychiatric disturbances. Our aim was to investigate if hepatocyte transplantation can prevent or minimize the metabolic alterations in an AIP mouse model. We transplanted wild-type hepatocytes into PBGD-deficient mice and induced heme synthesis with phenobarbital. ALA and PBG concentrations in plasma were monitored, and the gene transcriptions of hepatic enzymes ALAS1, PBGD, and CYP2A5 were analyzed. Results were compared with controls and correlated to the percentage of engrafted hepatocytes. The accumulation of ALA and PBG was reduced by approximately 50% after the second hepatocyte transplantation. We detected no difference in mRNA levels of PBGD, ALAS1, or CYP2A5. Engraftment corresponding to 2.7% of the total hepatocyte mass was achieved following two hepatocyte transplantations. A lack of precursor production in less than 3% of the hepatocytes resulted in a 50% reduction in plasma precursor concentrations. This disproportional finding suggests that ALA and PBG produced in PBGD-deficient hepatocytes crossed cellular membranes and was metabolized by transplanted cells. The lack of effect on enzyme mRNA levels suggests that no significant efflux of heme from normal to PBGD-deficient hepatocytes takes place. Further studies are needed to establish the minimal number of engrafted hepatocytes needed to completely correct the metabolic abnormality in AIP and whether amelioration of the metabolic defect by partial restoration of PBGD enzyme activity translates into a clinical effect in human AIP.
authors.affiliation: Division of Transplantation Surgery, Department for Clinical Science, Intervention and Technology CLINTEC, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Yin
authors.forename: Staffan
authors.initials: S
authors.lastname: Wahlin
authors.forename: Ewa C S
authors.initials: EC
authors.lastname: Ellis
authors.forename: Pauline
authors.initials: P
authors.lastname: Harper
authors.forename: Bo-Göran
authors.initials: BG
authors.lastname: Ericzon
authors.forename: Greg
authors.initials: G
authors.lastname: Nowak
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000235:genetics / Q000378:metabolism; D000622:Aminolevulinic Acid / Q000097:blood; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D011163:Hydroxymethylbilane Synthase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011162:Porphobilinogen / Q000097:blood; D017118:Porphyria, Acute Intermittent / Q000628:therapy*; D012333:RNA, Messenger / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D012333:RNA, Messenger; D011162:Porphobilinogen; D000622:Aminolevulinic Acid; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D000072467:Cytochrome P450 Family 2; D000624:5-Aminolevulinate Synthetase; D011163:Hydroxymethylbilane Synthase