Protoporphyrin accumulation

It is possible that lead s interference with heme synthesis may underlie the effects on vitamin D metabolism. Evidence that lead affects heme synthesis in the kidney was presented in the section on hematological effects. In addition, apparent thresholds for the effects of lead on renal vitamin D metabolism and for erythrocyte protoporphyrin accumulation are similar. 

Protoporphyrin accumulates in erythrocytes, bone marrow, and plasma. 

Bifenox, fluoroglycofen-ethyl, HC-252, lactofen, and oxyfluorfen have analogous structures and modes of action. The carboxyl group may be replaced by an ether group or an ester, and many other herbicides with related structures have been developed. Tetrapyrrol and protoporphyrin accumulate, act as photosensitizers, and cause photooxidation and necrosis. They are contact herbicides and are more active in strong sunlight. 

In hematopoietic cells, iron is used to produce hemoglobin through its combination with zinc protoporphyrin to form heme. Therefore, protoporphyrin accumulates relative to hemoglobin in red blood cells during iron deficiency. Mature red blood cells circulate in the body for approximately 120 days before being destroyed. Macrophage cells... 

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,... 

Scheme 4. The heme biosynthetic pathway. In vivo administration of d-aminolevulinic acid induces accumulation of fluorescent protoporphyrin IX (PpIX) preferably in malignant tissues...

Aminolevulinic acid (ALA HCl, Levulan Kerastick) is indicated for the treatment of nonhyperkeratotic actinic keratosis of the face and scalp. It has two components, an alcohol solution vehicle and ALA HCl as a dry solid. The two are mixed prior to application to the skin. When applied to human skin, ALA is metabolized to protoporphyrin, which accumulates and on exposure to visible light produces a photodynamic reaction that generates reactive oxygen species (ROS).The ROS produce cytotoxic effects that may explain therapeutic efficacy. Local burning and stinging of treated areas of skin due to photosensitization can occur. 

This mode of action has been shown to be very effective at controlling weeds with rates as low as 1 gha-1 leading to plant death for two good reasons. In the first place, there is little substrate competition with the herbicide because the substrate is lost to the cytoplasm when inhibition occurs and, second, because protoporphyrin IX will accumulate even... 

One of the rarer porphyrias results in an accumulation of uroporphyrinogen I, an abnormal isomer of a protoporphyrin precursor. This compound stains the urine red, causes the teeth to fluoresce strongly in ultraviolet light, and makes the skin abnormally sensitive to sunlight. Many individuals with this porphyria... 

Committed step in heme synthesis, its coenzyme, and inhibitor The committed step in heme synthesis is the formation of 5-amlnolevulinic acid (ALA). The reaction, which requires pyridoxal phosphate as a coenzyme, is catalyzed by ALA synthase. The reaction is inhibited by hemin (the oxidized form of heme that accumulates in the cell when it is being under-used). The conversion of protoporphyrin IX to heme, catalyzed by ferrochelatase, is inhibited by lead. 

Ferrochelatase (protoheme ferro-lyase)401 403 inserts Fe2+ into protoporphyrin IX to form heme. The enzyme is found firmly bound to the inner membrane of mitochondria of animal cells, chloroplasts of plants, and chromatophores of bacteria. While Fe2+ is apparently the only metallic ion ordinarily inserted into a porphyrin, the Zn2+ protoporphyrin chelate accumulates in substantial amounts in yeast, and Cu2+-heme complexes are known (p. 843). Ferrochelatase, whose activity is stimulated by Ca2+, appears to be inhibited by lead ions, a fact that may account for some of the acute toxicity of lead.404... 

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. 

Fig. 2 Examples of photosensitizers presently approved for clinical applications or in clinical studies. mTHPC, tetra (meso-hydroxy) phenyl chlorin BPD-MA, benzoporphyrin derivative Photofrin is a mixture of several compounds where dimers or trimers of the indicated structure are assumed to be of major importance PpIX, protoporphyrin IX - accumulating upon treatment with 5-aminolevulinic acid or its ester derivatives, NPe6, HPPH, Hexyl pyropheophorbide TPPS2a, disulfonated (adjacent) tetraphenylporphin AlPcS2a, disulfonated (adjacent) aluminum phthalocyanine. Areas with ionic side groups are indicated in shadow...

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