Physiologic Role of Heme and Cytochrome P-450 in Hematopoietic Cells

Abstract

Heme (ferroprotoporphyrin IX) is a ubiquitous molecule that serves as the prosthetic group of a variety of important hemoproteins that are essential for hemopoietic processes. Heme is involved in oxygen transport as the prosthetic group of hemoglobin, in prostaglandin synthesis as the prosthetic group of cyclooxygenase, in the enzymatic decomposition of H₂O₂ as the prosthetic group of catalase and peroxidase, and in the inactivation of oxygen molecules, as the prosthetic group of mitochondrial and microsomal cytochrome P-450. The latter refers to a family of isozymes for which heme serves as the prosthetic group that oxidizes a wide variety of structurally unrelated compounds, inactivates leukotrienes (leukotriene B4), and metabolizes arachidonic acid (AA) to bioactive metabolites, some of which are involved in the signal transduction process for hematopoietic growth factors. However, the effect of heme on erythropoiesis appears to be distinct from its direct involvement as a prosthetic group.

The expression of specific heme metabolic enzymes determines the level of cellular heme that is necessary for proper erythropoiesis. This concept is supported by evidence that hereditary or experimental alterations in enzymatic or biosynthetic events are often accompanied by a disturbance in heme levels, and that treatment with drugs or inhibitors of heme synthesis may affect progenitor cells, resulting in altered growth and differentiation (1). It is becoming increasingly evident that the role of heme metabolic enzymes in the regulation of hematopoiesis has a dual nature, since metabolic enzymes appear to participate in the implementation of both stimulation and suppression of erythropoiesis (1, 2). Enhancement of erythropoiesis obtained with the growth factors interleukin 3 and erythropoietin (Epo) also results in increased levels of δ-aminolevulinic acid synthase (ALAS) and porphobilinogen deaminase (PBGD), the proposed rate-limiting enzymes in the heme biosynthetic pathway.