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Lead Toxicity and Flavonoids
Published in Tanmoy Chakraborty, Lalita Ledwani, Research Methodology in Chemical Sciences, 2017
Amrish Chandra, Deepali Saxena
Ferrochelatase is the enzyme that catalyzes the incorporation of iron into the porphyrin ring. If as a result of lead toxicity, the enzyme is inhibited and its pathway is interrupted, or if adequate iron is not available, zinc is substituted for iron, and zinc protoporphyrin concentration is increased.42 The critical target, however, seems to be the enzyme’s haem synthesis, essential for the insertion of iron into the precursor, protoporphyrin IX. The major consequences of this effect, which have been evaluated in both adults and children, are reduction of hemoglobin and the inhibition of cytochrome P450-dependent phase-I metabolism. Lead inhibits normal hemoprotein function in both respects, which results in basophilic stippling of erythrocytes related to clustering of ribosome and microcytosis. The threshold for this effect in children is approximately 15 µg/dL.38,43
Controlled Drug Delivery in Photodynamic Therapy and Fluorescence-Based Diagnosis of Cancer
Published in Mary-Ann Mycek, Brian W. Pogue, Handbook of Biomedical Fluorescence, 2003
The most important approach in the PDT and PD of cancer using specific deficiencies of the metabolism of neoplastic cells is based on the systemic or topical administration of 5-aminolevulinic acid (ALA). ALA is not a photoactive substance by itself, but forms part of a substrate in the biosynthetic pathway of heme, the iron(II) complex of protoporphyrin IX (PpIX) (see Fig. 8). In contrast to heme, PpIX is a fluorescent molecule with a 1O2 quantum yield of approximately 0.5 [148], which makes it suitable for PDT and PD. Almost all nucleated cells in mammals exhibit the ability to produce PpIX. The route by which cells produce PpIX endogenously forms part of the overall scheme for the production of chemical energy. Nowadays the biosynthetic pathway of heme is relatively well understood and has been reviewed recently by Peng and coworkers [149]. In brief, the initial step in heme biosynthesis is the enzymatically catalyzed formation of ALA from glycine and succinyl-CoA inside the inner mitochondrial membrane. Following the entry of ALA into the cytosolic space, ALA dehydrase induces the condensation of two ALA molecules to form porphobilinogen (PBG). Subsequently, PBG deaminase (PBG-D) and uroporphyrinogen III cosynthase catalyze the cyclization of four PBG molecules to form the tetrapyrrolic skeleton. Finally, a series of decarboxylations and oxidations inside the cytoplasm as well as in the mitochondria have to take place before PpIX is formed, by the removal of six hydrogens from the protoporphyrinogen IX, catalyzed by protoporphyrinogen oxidase, which is embedded in the inner mitochondrial membrane. Ferrochelatase, also located in the inner mitochondrial membrane, catalyzes the incorporation of iron into the PpIX cycle to form nonfluorescent heme. Heme biosynthesis is regulated by numerous control mechanisms, among which is the negative feedback control on the ALA synthase (ALA-S) activity as well as on the transcription, translocation, and transport of the enzyme into the mitochondria.
Epigenetic modifications associated with pathophysiological effects of lead exposure
Published in Journal of Environmental Science and Health, Part C, 2019
Madiha Khalid, Mohammad Abdollahi
Hematopathological changes are observed among Pb-exposed animals. Pb has a high affinity for sulfhydryl groups, potentiating its toxic effect to multiple enzyme systems of heme biosynthesis. It interferes different phases of heme biosynthesis. It impairs cyclocondensation of two units of ALA to porphobilinogen via directly inhibiting cytosolic aminolevulinic acid dehydratase (ALAD). It increases coproporphyrin levels in urine by depressing coproporphyrin oxidase activity. Pb also impairs iron incorporation into the mitochondrial enzyme ferrochelatase and disrupts its activity. Ferrochelatase catalyzes Fe incorporation into protoporphyrin required for hemoglobin or other heme-containing enzymes, e.g., cytochrome c.83,261–264 It suppresses bone marrow hematopoiesis by impairing enteric Fe absorption.265–267 Higher BLLs are associated with a significant decline in the number of RBCs, hematocrit, and hemoglobin in both animals and humans.268–271 Pb exposure also affects band neutrophils and increases neutrophilopoiesis.272 It is associated with leucocytosis and an increased number of neutrophils and monocytes in young adult female mice.273 Lead exposure is reported to cause leucocytosis-mediated inflammation.269,274 Generally, infection is characterized by a change in the number, morphology and cellular function of leukocytes and an early infection displays an increase in the number of band neutrophils, metamyelocytes, young and immature WBCs. Peripheral blood smear analysis indicates Pb-induced abnormal hematopathological changes and risk of infection.265