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.