Variegate porphyria (VP) results from haploinsufficiency of
protoporphyrinogen oxidase (PPOX), the seventh
enzyme in the
heme synthesis pathway. There is no VP model that recapitulates the clinical manifestations of acute attacks. Combined administrations of 2-allyl-2-isopropylacetamide and
rifampicin in rabbits halved hepatic PPOX activity, resulting in increased accumulation of a potentially neurotoxic
heme precursor, lipid peroxidation,
inflammation, and hepatocyte cytoplasmic stress. Rabbits also showed
hypertension, motor impairment, reduced activity of critical mitochondrial hemoprotein functions, and altered
glucose homeostasis.
Hemin treatment only resulted in a slight drop in
heme precursor accumulation but further increased hepatic
heme catabolism,
inflammation, and cytoplasmic stress.
Hemin replenishment did protect against
hypertension, but it failed to restore action potentials in the sciatic nerve or
glucose homeostasis. Systemic
porphobilinogen deaminase (PBGD)
mRNA administration increased hepatic PBGD activity, the third
enzyme of the pathway, and rapidly normalized serum and urine
porphyrin precursor levels. All features studied were improved, including those related to critical hemoprotein functions. In conclusion, the VP model recapitulates the biochemical characteristics and some clinical manifestations associated with severe acute attacks in humans. Systemic PBGD
mRNA provided successful protection against the acute attack, indicating that PBGD, and not PPOX, was the critical
enzyme for hepatic
heme synthesis in VP rabbits.