Protoporphyrin IX

About: Protoporphyrin IX is a research topic. Over the lifetime, 2250 publications have been published within this topic receiving 65544 citations. The topic is also known as: PpIX.

TMEM14C is required for erythroid mitochondrial heme metabolism.

Abstract: The transport and intracellular trafficking of heme biosynthesis intermediates are crucial for hemoglobin production, which is a critical process in developing red cells. Here, we profiled gene expression in terminally differentiating murine fetal liver-derived erythroid cells to identify regulators of heme metabolism. We determined that TMEM14C, an inner mitochondrial membrane protein that is enriched in vertebrate hematopoietic tissues, is essential for erythropoiesis and heme synthesis in vivo and in cultured erythroid cells. In mice, TMEM14C deficiency resulted in porphyrin accumulation in the fetal liver, erythroid maturation arrest, and embryonic lethality due to profound anemia. Protoporphyrin IX synthesis in TMEM14C-deficient erythroid cells was blocked, leading to an accumulation of porphyrin precursors. The heme synthesis defect in TMEM14C-deficient cells was ameliorated with a protoporphyrin IX analog, indicating that TMEM14C primarily functions in the terminal steps of the heme synthesis pathway. Together, our data demonstrate that TMEM14C facilitates the import of protoporphyrinogen IX into the mitochondrial matrix for heme synthesis and subsequent hemoglobin production. Furthermore, the identification of TMEM14C as a protoporphyrinogen IX importer provides a genetic tool for further exploring erythropoiesis and congenital anemias.

Photosensitization in Porphyrias and Photodynamic Therapy Involves TRPA1 and TRPV1

Abstract: Photosensitization, an exaggerated sensitivity to harmless light, occurs genetically in rare diseases, such as porphyrias, and in photodynamic therapy where short-term toxicity is intended. A common feature is the experience of pain from bright light. In human subjects, skin exposure to 405 nm light induced moderate pain, which was intensified by pretreatment with aminolevulinic acid. In heterologous expression systems and cultured sensory neurons, exposure to blue light activated TRPA1 and, to a lesser extent, TRPV1 channels in the absence of additional photosensitization. Pretreatment with aminolevulinic acid or with protoporphyrin IX dramatically increased the light sensitivity of both TRPA1 and TRPV1 via generation of reactive oxygen species. Artificial lipid bilayers equipped with purified human TRPA1 showed substantial single-channel activity only in the presence of protoporphyrin IX and blue light. Photosensitivity and photosensitization could be demonstrated in freshly isolated mouse tissues and led to TRP channel-dependent release of proinflammatory neuropeptides upon illumination. With antagonists in clinical development, these findings may help to alleviate pain during photodynamic therapy and also allow for disease modification in porphyria patients. SIGNIFICANCE STATEMENT Cutaneous porphyria patients suffer from burning pain upon exposure to sunlight and other patients undergoing photodynamic therapy experience similar pain, which can limit the therapeutic efforts. This study elucidates the underlying molecular transduction mechanism and identifies potential targets of therapy. Ultraviolet and blue light generates singlet oxygen, which oxidizes and activates the ion channels TRPA1 and TRPV1. The disease and the therapeutic options could be reproduced in models ranging from isolated ion channels to human subjects, applying protoporphyrin IX or its precursor aminolevulinic acid. There is an unmet medical need, and our results suggest a therapeutic use of the pertinent antagonists in clinical development.

Photochemotherapeutic method using 5-aminolevulinic acid and precursors thereof

Abstract: Medicaments for detecting and treating malignant and non-malignant tissue abnormalities and lesions of the skin; conjunctiva; respiratory, digestive and vaginal mucosa; endometrium and urothelium; and for ablating the endometrial tissue and treating body fluids containing suspended abnormal cells, and for treating cancers of the nervous system are prepared from 5-aminolevulinic acid or precursor thereof and subsequently administered to the patient in an amount sufficient to induce syntheses fluorescence and/or photosensitizing concentrations or protoporphyrin IX in the abnormal cells, followed by exposure of the abnormal cells to light of photoactivating wavelengths

Interstitial photodynamic therapy in the canine prostate with disulfonated aluminum phthalocyanine and 5-aminolevulinic acid-induced protoporphyrin IX

Abstract: BACKGROUND Photodynamic therapy (PDT) is an experimental approach for treating prostate cancer localized to the gland that does not involve surgery or irradiation. Second-generation photosensitizers 5-aminolevulinic acid (ALA) and aluminum disulfonated phthalocyanine (A1S2Pc) were studied in the normal canine prostate. METHODS Tissue biodistribution of photosensitizers on serial biopsies was examined using fluorescence microscopy. Photodynamic therapy was done by delivering red light interstitially at 100mW through fibers placed under transrectal ultrasound guidance. RESULTS Peak levels of A1S2Pc apppeared at 5-24 hr and at 3 hr for ALA. Macroscopic PDT lesions were up to 12 mm in diameter using A1S2Pc, but only 1-2 mm with ALA. Light at 300 mW caused thermal lesions. At 28 days, damaged glands remained atrophic, but the interlobular supporting stroma was well preserved. Urethral lesions healed by 28 days without functional impairment. CONCLUSIONS Although the results with ALA were disappointing, PDT using A1S2Pc looks like a promising modality for treatment of localized prostate cancer. Prostate 32:89–98, 1997. © 1997 Wiley-Liss, Inc.