Protoporphyrins in erythrocyte

Inhibition of ferrochelatase in the heme pathway causes accumulation of protoporphyrin in erythrocytes (CDC 1985). Most protoporphyrin in erythrocytes (about 90%) exists as zinc protoporphyrin (ZnPP). This fraction is preferentially measured by hematofluorometers. Extraction methods measure all the protoporphyrin present, but strip the zinc from the ZnPP during the extraction process. For this reason,... 

Chisolm JJ Jr, Brown DH. 1979. Micromethod for zinc protoporphyrin in erythrocytes Including new data on the absorptivity of zinc protoporphyrin and new observation in neonates and sickle cell disease. Biochem Med 22 214-237. 

Chromatographic determination of protoporphyrins in erythrocytes has the same indications as the spectrophotometric one. In addition, the method enables the differentiation between zinc-protoporphyrin and (metal-)free protoporphyrin. The first is elevated in iron deficiency and lead intoxication, the second in erythropoietic protoporphyria. 

Table 7.3.7 Standard solutions used in the HPLC determination of protoporphyrins in erythrocytes...

Each laboratory should establish its own reference values. Those given below can only be interpreted as a guide. Free protoporphyrins in erythrocytes are rarely detectable in healthy individuals. Zinc protoporphyrin <1.3 pmol/1 (mean 2SD), free protoporphyrin < 0.2 pmol/1 (detection limit). 

The insertion of ferrous iron into the porphyrin ring in the biosynthesis of heme is catalyzed by the enzyme ferrochelatase. A deficiency in ferrochelatase activity results in an accumulation or the excretion of unchelated protoporphyrin in patients with erythrohepatic protoporphyria. Ferrochelatase catalyzes the synthesis of a range of metalloporphyrins,628 and, for example, produces zinc protoporphyrin in erythrocytes of patients with iron-deficiency anaemia. 

FECH (also known as heme synthase) is an iron-sulfur protein located in the inner mitochondrial membrane. This enzyme inserts ferrous iron into protoporphyrin to form heme During this process, two hydrogens are displaced from the ring nitrogens. Other metals in the divalent state will also act as substrate, yielding the corresponding chelate (e.g., incorporation of Zn into protoporphyrin to yield zinc protoporphyrin). In iron-deficient states Zn successfully competes with Fe in developing red cells so that the concentration of zinc protoporphyrin in erythrocytes increases. Furthermore, other dicarboxylic porphyrins will also serve as substrates (e.g., mesoporphyrin). 

Lead exposure mcreases urinary ALA and coproporphyrin-III excretion and causes accumulation of 2n-protoporphyrin in erythrocytes. The definitive test for lead toxicity is measurement of blood lead, but occasionally lead exposure is responsible for porphyria-like symptoms and may be an unexpected finding when investigating patients for suspected porphyria. ... 

Hart D, Piomelli S. Simultaneous quantitation of zinc protoporphyrin and free protoporphyrin in erythrocytes by acetone extraction. Clin Chem 1981 27 220-2. 

Lead (Pb) inhibits poiphobilinogen synthase and Fe" incorporation into haem, resulting in increased levels of 5-aminolaevulinic acid and coproporphyrin in urine and protoporphyrin in erythrocytes. 

Ferrochelauise (EC 4.99.1.1). Activity greatly decreased in bone marrow and liver. High levels of protoporphyrin in erythrocytes, normoblasts and feces. Mild photodermatosis. Erythema and pruritis. Mild edema. Usually cholelithiasis. Sometimes liver failure. Treatment by oral administration of -carotene, and protection from UV light. Autosomal dominant. 

Lead interference with the insertion of iron into protoporphyrin results in an accumulation of protoporphyrin in erythrocytes (red blood cells). It appears that free erythrocyte protoporphyrin (FEP) begins to increase at a PbB of 17-20 Mg (100 ml) in children and women, and at slightly higher levels of 20-25 Mg (100 ml)" in adult males [6], although these thresholds are ill-defined and are still open to question. This accumulation of FEP has been taken by the... 

Zinc protoporphyrin in blood After 1 month exposure 2 50 pg/100 ml erythrocytes or lOOpg/IOOmI blood B... 

Hammond PB, Bomschein RL, Succop P. 1985. Dose-effect and dose-response relationships of blood lead to erythrocytic protoporphyrin in young children. In Bomschein RL, Rabinowitz MB, eds. The Second International Conference on Prospective Studies of Lead, Cincinnati, OH April, 1984. Environ Res 38 187-196. 

Protoporphyrin accumulates in erythrocytes, bone marrow, and plasma. 

Griseofulvin interferes with porphyrin metabolism. In man, transient increases in erythrocyte protoporphyrin concentrations have been demonstrated, and the production and excretion of porphyrins is increased. Acute intermittent porphyria is an absolute contraindication to griseofulvin. In patients with other forms of porphyria it should also be avoided, in view of the many alternatives (458-463). 

The primary biochemical abnormality in EPP is decreased FECH activity. Although this decrease is present in aU tissue, the excess protoporphyrin is formed mainly in erythroid cells. Accumulation of protoporphyrin in the liver is the result of failure of the fiver to excrete the increased load it receives from release of protoporphyrin from erythrocytes and their immediate precursors. 

Krieg, M. and Whitten, D.G. (1984a) Self-sensitized photo-oxidation of protoporphyrin IX and related porphyrins in erythrocyte ghosts and microemulsions a novel photooxidation pathway involving singlet oxygen, J. Photochem., 25 235-252. 

An example of an indirect marker of xenobiotic-in-duced renal disease is the elevated level of red cell content of either delta amino-levulinic acid dehydrase or free erythrocyte protoporphyrin in patients with lead nephrotoxicity [3,4]. Direct examples of biomarkers of... 

The concentration of lead in blood is an indication of recerd absorption of the metal. Clinical manifestations associated with increasing concentrations of lead in blood are shown in Figure 65-2. Children with concentrations of lead in blood >10 pg/dL are at risk ( developmental disabilities. Adults with concentrations <30 pg/dL exhibit no known functional injury or symptoms however, they will have a definite decrease in S-ALA dehydratase activity, a slight increase in urinary excretion of S-ALA, and an increase in erythrocyte protoporphyrin. Patients with a blood lead concentration of 30-75 pg/dL have all the preceding laboratory abnormalities and, usually, nonspecific, mild symptoms of lead poisoning. Clear symptoms of lead poisoning are associated... 

The alteration of the enzymatic activity of ferrochelatase due to the inhibition of this enzyme by the effect of Pb produces an increase in the protoporphyrin IX concentration in erythrocytes. This increase of protoporphyrin IX produces and accumulation of Zn-protoporphyrin I due to the complexation formation of this porphyrin with Zn. ... 

LA Control group. The results of the control group for Pb in blood and in 24 hours urine are shown in Table I. In Table 2 are presented the values of ALA-D and protoporphyrin IX in erythrocytes for the same population and in Table III those of the hemoglobin concentration and protoporphirin IX/g of haemoglobin coefficient. In table 4 are indicated the values of 5-ALA and porphobilinogen (PEG) in 24 hours urine and in the last (table 5) are presented the results found in urine of 24h of uroporphyrins and coproporphyrins. 

The identification and quantification of high levels of porphyrins in erythrocytes, mainly protoporphyrin IX and its chelated form, Zn-protoporphyrin, are essentials in the diagnosis of Pb poisoning and in erythropoietic porphyrias (Meyer et al., 1980b). 

Analogs of griseofulvin prepared by modification of the 5 position proved to be less active than the parent compound in vitro and in vivo. ° In 3 of 14 patients treated with oral griseofulvin, there was a rise in erythrocyte protoporphyrin that may have been secondary to hepatic toxicity. Griseofulvin has been reported as effective in the treatment of Raynaud s disease, a vasospastic disorder. ... 

Inhibition of heme synthetase Various BLL threshold 17 pg/dL Onset of rise in erythrocyte protoporphyrin begins at this BLL. Basis of ZPP tesE evidence of toxicity at BLLs that may occur on firing ranges. Piomelli et al. 1973, 1982... 

---