Protoporphyrin IX: the Good, the Bad, and the Ugly

Abstract

Protoporphyrin IX (PPIX) is ubiquitously present in all living cells in small amounts as a precursor of heme. PPIX has some biologic functions of its own, and PPIX-based strategies have been used for cancer diagnosis and treatment (the good). PPIX serves as the substrate for ferrochelatase, the final enzyme in heme biosynthesis, and its homeostasis is tightly regulated during heme synthesis. Accumulation of PPIX in human porphyrias can cause skin photosensitivity, biliary stones, hepatobiliary damage, and even liver failure (the bad and the ugly). In this work, we review the mechanisms that are associated with the broad aspects of PPIX. Because PPIX is a hydrophobic molecule, its disposition is by hepatic rather than renal excretion. Large amounts of PPIX are toxic to the liver and can cause cholestatic liver injury. Application of PPIX in cancer diagnosis and treatment is based on its photodynamic effects.

Fig. 1.

PPIX/heme biosynthesis and disposition in mammalian cells. Multiple enzymes, cofactors, and transporters are involved in the pathway of PPIX/heme biosynthesis and in PPIX disposition. CPOX, coproporphyrinogen oxidase; FLVCR1, feline leukemia virus subgroup c receptor 1; HMBS, hydroxymethylbilane synthase; PLP, pyridoxal phosphate; SLC25A38, solute carrier family 25 member 38; UROD, uroporphyrinogen decarboxylase; UROS, uroporphyrinogen III synthase.

Fig. 2.

Regulation of PPIX homeostasis. Genetic factors and xenobiotics can disturb PPIX homeostasis through effects on (1) ALAS, (2) FECH, (3) iron supply, (4) PPIX transporters, (5) pyridoxal phosphate (PLP; the cofactor of ALAS), and (6) the enzymes and transporters downstream of ALAS and upstream of FECH.

Fig. 3.

Mechanisms of PPIX-mediated liver injury and strategies to manage this injury. PPIX-mediated hepatocyte and cholangiocyte damage initiates hepatobiliary injury in EPP. Approaches to manage this condition have included (1) suppression of PPIX biosynthesis by hemin; (2) plasmapheresis; (3) vitamin E or N-acetyl cysteine to reduce oxidative stress; (4) ursodeoxycholic acid to increase bile flow and PPIX excretion; (5) activated charcoal or cholestyramine to prevent reabsorption of PPIX from the small intestine; (6) liver transplantation; (7) bone marrow transplantation to restore FECH function; and in preclinical models (8) gene therapy targeting FECH.