Porphyria Educational Services

PORPHYRIA EDUCATIONAL SERVICES BULLETIN
Vol. 2 No. 22 May 28, 2000
FOCUS: Heme, Cytochrome P-450 and Porphyria

Heme Biosynthesis is the backbone of the porphyrias.

Heme is synthesized in largest amounts by the bone marrow. In the bone marrow the heme is incorporated into hemoglobin. The hemoglobin which is an oxygen transport protein takes it from there.

The heme is then off to the liver. At the liver the heme is metabolized by the liver, where most of the heme is incorporated into cytochromes.

The cytochromes are electron transport proteins. The most abundant cytochromes in liver are the cytochrome P-450 enzymes that metabolize drugs and many other foreign and endogenous chemicals. It is for this reason that all porphyrics must be very careful in avoiding all drugs that metabolize in the liver. They are often referred to as P-450 drugs or toxins.

Heme biosynthesis is controlled differently in liver and bone marrow. Hepatic heme biosynthesis is rate-limited and primarily regulated by the first enzyme, ALA synthase. This enzyme's activity in liver cells is normally very low but increases dramatically by induction of enzyme synthesis when the liver produces more heme. Certain drugs and hormones induce hepatocytes to make more ALA synthase, heme, and cytochrome P-450.

In the bone marrow, heme is made in erythroblasts and reticulocytes that still contain mitochondria, whereas circulating erythrocytes lack mitochondria and cannot form heme.

Bone marrow cells express erythroid-specific forms of some pathway enzymes.

Porphyrias and related disorders are associated with deficiencies of the other seven enzymes, and mutations in genes for these enzymes have been characterized in detail in previous PES bulletins.

Although each type of hereditary porphyria is associated with deficiency of a particular enzyme, unless people with that enzyme deficiency come from the same family, they are likely to have different mutations in the gene for that enzyme. Because of this factors these diseases are heterogeneous at the molecular level.

Some porphyrias, especially those that increase the early precursors ALA and PBG, damage nerves, leading to a variety of symptoms such as abdominal pain and muscle weakness, which can even progress to paralysis.

Mechanisms for the neurologic disturbances have been speculated, such as effects of excessive heme pathway intermediates, or deficient heme synthesis, in the nervous system. ALA and other products of the heme biosynthetic pathway have not been proven to be neurotoxic, and heme deficiency in nervous tissue in these disorders is also unproven. Therefore, the exact cause remains unclear.