Porphyrias

Chick embyro liver cells in primary culture can be used in a sensitive test to determine the drugs or chemicals that can induce hepatic porphyria. The compounds are incorporated into the growth medium at a concentration of 0.5 to 100 xg/ml. The cells are examined 18 to 20 hours afterward with a fluorescence microscope. Granick [24,25] found that the inducing substance induce a de novo synthesis of ALA-synthe-tase, the limiting enzyme of the heme biosynthetic chain. As a result, ALA is greatly increased and is converted in part into porphyrins which are visualized as red fluorescent material in the cytoplasm of individual hepatic cells. 

Localization of Enzymes of the Heme Biosynthetic Chain in the Liver Cell 

The enzymes of the heme biosynthetic chain have a special distribution [Sano and Granick, 26]. Of the eight enzymes (Fig. 2), the first enz)Tne, ALA-synthetase, is found mainly in the mitochondria. The next four enzymes that convert ALA to coproporphyrinogen isomer III are localized in the cytosol that is, they are soluble enzymes. The last three enzymes are in the mitochondria—the two that oxidize, decarb-oxylate, and dehydrate coproporphyrinogen to protoporphyrinogen. 

As a result of such methods it was concluded that four of the eight enzymes of the heme biosynthetic chain are localized inside the inner membrane of the mitochondrion, whereas the other four enzymes reside in the cytosol. 

What is the significance of this distribution of the enzymes of the heme biosynthetic chain It is obvious that the location of ALA-synthetase within the inner mitochondrial membrane, adjacent to the 

---

Iron Porphyrins. Porphyrias (15—17) are aromatic cycHc compouads that coasist of four pyrrole units linked at the a-positions by methine carbons. The extended TT-systems of these compounds give rise to intense absorption bands in the uv/vis region of the spectmm. The most intense absorption, which is called the Soret band, falls neat 400 nm and has 10. The TT-system is also responsible for the notable ring current effect observed in H-nmr spectra, the preference for planar conformations, the prevalence of electrophilic substitution reactions, and the redox chemistry of these compounds. Porphyrins obtained from natural sources have a variety of peripheral substituents and substitution patterns. Two important types of synthetic porphyrins are the meso-tetraaryl porphyrins, such as 5,10,15,20-tetraphenylporphine [917-23-7] (H2(TPP)) (7) and P-octaalkylporphyrins, such as 2,3,7,8,12,13,17,18-octaethylporphine [2683-82-1] (H2(OEP)) (8). Both types can be prepared by condensation of pyrroles and aldehydes (qv). 

These dru are contraindicated in patients with known hypersensitivity. Hydroxychloroquine is contraindicated in patients with porphyria (a group of serious inherited disorders affecting the bone marrow or the liver), psoriasis (chronic skin disorder), and retinal disease (may cause irreversible retinal damage). MTX is contraindicated during pregnancy because it is a Pregnancy Category X dmg and may cause birth defects... 

The studies on the effect of brominated aromatic compounds on the activity of ALA-D and ALA-S provide an introduction to the examination of porphyrogenic effect of these compounds. Disturbance in these enzymes as well as in URO decarboxylase activity according to some authors, might function as an introduction in development of liver porphyrias. 

Knowledge of the biochemistry of the porphyrins and of heme is basic to understanding the varied functions of hemoproteins (see below) in the body. The porphyrias are a group of diseases caused by abnormalities in the pathway of biosynthesis of the various porphyrins. Although porphyrias are not very prevalent, physicians must be aware of them. A much more prevalent clinical condition is jaundice, due to elevation of bilirubin in the plasma. This elevation is due to overproduction of bilirubin or to failure of its excretion and is seen in numerous diseases ranging from hemolytic anemias to viral hepatitis and to cancer of the pancreas. 

The importance of some of these regulatory mechanisms is further discussed below when the porphyrias are described. 

The porphyrias are a group of disorders due to abnormalities in the pathway of biosynthesis of heme they can be genetic or acquired. They are not prevalent, but it is important to consider them in certain circumstances (eg, in the differential diagnosis of abdominal... 

Biochemistry Underlies the Causes, Diagnoses, Treatments of the Porphyrias... 

In general, the porphyrias described are inherited in an autosomal dominant manner, with the exception of congenital erythropoietic porphyria, which is inherited in a recessive mode. The precise abnormalities in the genes directing synthesis of the enzymes involved in heme biosynthesis have been determined in some instances. Thus, the use of appropriate gene probes has made possible the prenatal diagnosis of some of the porphyrias. 

As is true of most inborn errors, the signs and symptoms of porphyria result from either a deficiency of metabohc products beyond the enzymatic block or from an accumulation of metabolites behind the block. 

If the enzyme lesion occurs early in the pathway prior to the formation of porphyrinogens (eg, enzyme 3 of Figure 32-9, which is affected in acute intermittent porphyria), ALA and PBG will accumulate in body tissues and fluids (Figure 32-11). Glinically, patients complain of abdominal pain and neuropsychiatric symptoms. The precise biochemical cause of these symptoms has not been determined but may relate to elevated levels of ALA or PBG or to a deficiency of heme. 

Figure 32-11. Biochemical causes of the major signs and symptoms of the porphyrias.

ALA dehydratase deficiency (hepatic) (MIM 125270) Acute intermittent porphyria (hepatic) (MIM 176000) Congenital erythropoietic (erythropoietic) (MIM 263700)... 

Porphyria cutanea tarda (hepatic) (MIM 176100) Hereditary coproporphyria (hepatic) (MIM 121300)... 

Only the biochemical findings in the active stages of these diseases are listed. Certain biochemical abnormalities are detectable in the latent stages of some of the above conditions. Conditions 3,5, and 8 are generally the most prevalent porphyrias. 

X-linked sideroblastic anemia is not a porphyria but is included here because 6-aminolevulinic acid synthase is involved. 

The diagnosis of a specific type of porphyria can generally be established by consideration of the chnical and family history, the physical examination, and appropriate laboratory tests. The major findings in the six principal types of porphyria are listed in Table 32-2. 

It is hoped that treatment of the porphyrias at the gene level will become possible. In the meantime, treatment is essentially symptomatic. It is important for patients to avoid drugs that cause induction of cyto-... 

Anderson KE et al Disorders of heme biosynthesis X-linked sideroblastic anemia and the porphyrias. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001. 

Elder GH Haem synthesis and the porphyrias. In Scientific Foundations of Biochemistry in Clinical Practice, 2nd ed. Williams DL, Marks V (editors). Butterworth-Heinemann, 1994. 

---