We previously reported that the expression and activity of the hemeprotein cytochrome c oxidase is elevated in ALA-treated cells. Therefore, the addition of ALA to cells might promote the biosynthesis of heme, and we hypothesized that activating heme synthesis increases the expression and activity of hemeproteins. ALA synthesis is the rate-limiting step of this pathway. Following some steps, ALA is returned to the mitochondria where it is converted to PpIX, which is converted to heme by binding ferrous ion. ALA is synthesized from glycine and succinyl CoA in the mitochondria and is then transported to the cytoplasm. 5-Aminolevulinic acid (ALA) is a well-known precursor in the protoporphyrin IX (PpIX) synthesis pathway leading to the synthesis of heme. Therefore, we assumed that hemeprotein activity might be affected by increasing or decreasing the intracellular levels of heme. The mono-oxygenase activities of CYPs require the heme prosthetic group. Further, CYP2A6 hydroxylates the anticancer prodrug tegafur, which converts it to the cytotoxic metabolite 5-fluorouracil (5-FU). For example, the widely used anticancer prodrug cyclophosphamide is activated mainly by 4-hydroxylation reactions catalyzed by CYP2B6, CYP2C19, and CYP3A4. However, CYPs also convert nontoxic prodrugs to cytotoxic metabolites, and many of these drugs are used to treat cancer. In general, the metabolism of drugs by CYPs mainly leads to drug inactivation and facilitates the elimination of drugs from the body. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.Ĭytochrome P450 (CYP) is a hemeprotein, virtually present in all organisms, that catalyzes the oxidation of endogenous and xenobiotic lipophilic substrates. The specific roles of these authors are articulated in the author contributions section. The specific roles of these authors are articulated in the author contributions section.Ĭompeting interests: SBI Pharma CO., LTD., provided support in the form of salaries for authors MN and TT, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. SBI Pharma CO., LTD., provided support in the form of salaries for authors MN and TT, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. 26430141) from the Ministry of Education, Culture, Sports, Science and Technology.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedĭata Availability: All relevant data are within the paper.įunding: The studies in the authors’ laboratories were supported by the Grant-in-Aid for Scientific Research (C) (No. Received: MaAccepted: JPublished: July 16, 2015Ĭopyright: © 2015 Miura et al. PLoS ONE 10(7):Įditor: Aditya Bhushan Pant, Indian Institute of Toxicology Reserach, INDIA Citation: Miura M, Ito K, Hayashi M, Nakajima M, Tanaka T, Ogura S-i (2015) The Effect of 5-Aminolevulinic Acid on Cytochrome P450-Mediated Prodrug Activation.
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