Porphyria synthesis

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. 

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. 

The nature of the molecular defect Is unclear and presumably lies In the repression mechanism for the gene controlling formation of the enzyme protein. Exposure to any of the drugs listed In Table V results In further marked de-repressIon of enzyme synthesis and severe porphyria. 

Haem synthesis is a good example of a pathway that is partly compartmentalized. The pathway (Figure 5.16) occurs in all cell types for the production of respiratory cytochromes and begins within mitochondria but the majority of the reactions occur in the cytosol cell. Because mature red cells have no subcellular organelles, haem synthesis occurs only in early RBC progenitor cells. Although this is a relatively simple pathway, there are a number of well-known enzyme defects that cause a group of diseases called the porphyrias. 

There are a large number of hereditary or acquired disturbances of porphyrin synthesis, known as porphyrias, some of which can cause severe clinical pictures. Several of these diseases lead to the excretion of heme precursors in feces or urine, giving them a dark red color. Accumulation of porphyrins in the skin can also occur, and exposure to light then causes disfiguring, poorly healing blisters. Neurological disturbances are also common in the porphyrias. 

Barbiturates generally increase the synthesis of porphyrin and intermittent porphyria is therefore an absolute contraindication for their use. 

Porphyrias are caused by inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors (see Summary Figure 21.7). With the exception of congenital erythropoietic porphyria, which is a genetically recessive disease, all porphyrias are inherited as autosomal dominant disorders. The mutations that cause the porphyrias are heterogenous (not all are at the same DNA locus), and nearly every affected family has its own mutation. Each porphyria results in the accumulation of a unique pattern of intermediates caused by the deficiency of an enzyme in the heme synthetic pathway. 

Increased ALA synthase activity One common feature of the j porphyrias is a decreased synthesis of heme. In the liver, heme normally functions as a repressor of ALA synthase. Therefore, Ihe absence of this end product results in an increase in the synthesis of ALA synthase (derepression). This causes an increased syn thesis of intermediates that occur prior to the genetic block. The accumulation of these toxic intermediates is the major pathophysi ology of the porphyrias. 

Some mild forms of intermittent porphyria may go unrecognized. However, ingestion of drugs can precipitate an acute attack, probably by inducing excessive synthesis of 8-aminolevulinate synthase. Among compounds having this effect are hexachlo-robenzene and tetrachlorodibenzodioxin. 

Thiopental may reduce hepatic blood flow and glomerular filtration rate, but it produces no lasting effects on hepatic and renal function. Barbiturates may exacerbate acute intermittent porphyria by inducing the synthesis of hepatic ALA synthase (see Chapter 22 Sedative-Hypnotic Drugs). Thiopental has precipitated porphyric crisis when used as an induction agent in susceptible individuals. 

Precautions As noted previously, barbiturates induce the P-450 system and therefore may decrease the effect of drugs that are metabolized by these hepatic enzymes. Barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria. 

Only phenobarbital strongly induces the synthesis of the hepatic cytochrome P-450 drug metabolizing system. Phenobarbital is contraindicated in the treatment of acute intermittent porphyria. Buspirone lacks the anticonvulsant and muscle-relaxant properties of the benzodiazepines and causes only minimal sedation, v ... 

Acute hereditary porphyrias are disorders of heme synthesis in which overproduction of heme precursors is often accompanied by severe clinical manifestations. Most of the time these diseases remain clinically latent and only occasionally result in acute abdominal and neuropsychiatric symptoms. Occurrence of the symptoms often follows exposure to drugs, such as barbiturates, sulfonamides, estrogens and some local anesthetics (Blanloeil et al. 1989). 

Excessive production of liver 5-aminolevulinate synthase causes two forms of congenital porphyria. These diseases are characterized by overproduction of porphyrins and excretion of large amounts of 5-aminolevulinate and porphobilinogen. Some ethnic groups have a high incidence of this disease, and in these people, acute attacks are brought on by barbiturates and other compounds that induce synthesis of the enzyme. 

The porphyrias are a heterogeneous group of inherited disorders of haem biosynthesis. Figure A9.1 shows the pathway of haem synthesis. A deficiency in one of the enzymes results in a specific porphyria. 

Figure A9.1 Pathway of haem synthesis. Blocks at various parts of the pathway result in different porphyrias (numbers in parentheses show inheritance). AR, autosomal recessive AD, autosomal dominant. (From Thadani et al., 2000, reproduced with permission.)...

In healthy people, forming haemoglobin for their erythrocytes and haem-dependent enzymes, the rate of haem synthesis is controlled by negative feedback according to the amount of haem present. When more haem is needed there is increased production of the rate-controlling enzyme delta-aminolaevulinic acid (ALA) synthase which provides the basis of the formation of porphyrin precursors of haem. But in people with porphyria one or other of the enzymes that convert the various porphyrins to haem is deficient and so porphyrins accumulate. A vicious cycle occurs less haem —> more ALA synthase —> more porphyrin precursors, the metabolism of which is blocked, and a clinical attack occurs. 

Primary porphyrias are caused by hereditary enzyme defects in haem synthesis. They can be differentiated clinically into acute and chronic porphyrias as well as pathogenetically into hepatic and erythropoietic porphyrias. Secondary porphyrias are symptomatic porphyrias present in various diseases or caused by poisoning or chemical substances, particularly alcohol. Depending on the preferred manifestation site of the enzyme defect, either in the hepatocytes or erythrocytes (bone marrow), the porphyrias are subdivided into hepatic, erythropoietic and hepatoerythropoietic forms. However, this classification is not always strictly applicable. Based on the course of disease, acute and chronic forms may be differentiated in primary hepatic porphyrias. The acute form is characterized by a congenital reg-... 

In porphyria cutanea tarda, iron deposition in the liver is generally low to moderate, predominantly in the hepa-tocytes of the acinar periphery. The cause is thought to be reduced activity of uroporphyrinogen decarboxylase resulting in decreased synthesis of porphyrin and haem. However, this variant of hepatic siderosis only becomes manifest as a result of various triggering factors. Treatment is also based on venesection. 

---