Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Feb;356(2):267-75.
doi: 10.1124/jpet.115.228130. Epub 2015 Nov 20.

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

Madhav Sachar  1 , Karl E Anderson  1 , Xiaochao Ma  2
Affiliations
Review

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

Madhav Sachar et al. J Pharmacol Exp Ther. 2016 Feb.

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.

PubMed Disclaimer

Figures

Fig. 1.
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.
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.
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ajioka RS, Phillips JD, Kushner JP. (2006) Biosynthesis of heme in mammals. Biochim Biophys Acta 1763:723–736. - PubMed
    1. Akilov OE, Kosaka S, O’Riordan K, Song X, Sherwood M, Flotte TJ, Foley JW, Hasan T. (2006) The role of photosensitizer molecular charge and structure on the efficacy of photodynamic therapy against Leishmania parasites. Chem Biol 13:839–847. - PubMed
    1. Amo T, Kawanishi N, Uchida M, Fujita H, Oyanagi E, Utsumi T, Ogino T, Inoue K, Shuin T, Utsumi K, and Sasaki J (2009) Mechanism of cell death by 5-aminolevulinic acid-based photodynamic action and its enhancement by ferrochelatase inhibitors in human histiocytic lymphoma cell line U937. Cell Biochem Funct 27:503–515. - PubMed
    1. Anderson KE, Drummond GS, Freddara U, Sardana MK, Sassa S. (1981) Porphyrogenic effects and induction of heme oxygenase in vivo by delta-aminolevulinic acid. Biochim Biophys Acta 676:289–299. - PubMed
    1. Anderson KE, Freddara U, Kappas A. (1982) Induction of hepatic cytochrome P-450 by natural steroids: relationship to the induction of δ-aminolevulinate synthase and porphyrin accumulation in the avian embryo. Arch Biochem Biophys 217:597–608. - PubMed

Publication types