| Fate of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET18-OME) in malignant cells, normal cells, and isolated and perfused rat liver. | |
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MedLine Citation:
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PMID: 7720513 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Ether lipids show high specific cytotoxicity in vitro on a wide variety of experimental tumors, but only moderate activity in vivo. One reason for this lack of activity in the whole animal might be a high degree of metabolic degradation. We therefore studied the biotransformation of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine ([3H]ET18-OMe) labeled in position 9-10 of the 1-alkyl chain, in rat plasma and erythrocytes, HL60 and K562 leukemic cells, HT29 adenocarcinoma cells, and cultured hepatocytes at 37 degrees C, and in a system of isolated and perfused rat liver. ET18-OMe and its metabolites were identified and quantified after lipid extraction and TLC separation. In tumor cells, 98% of ET18-OMe remained almost unmodified in vitro after 24-hr incubation. Plasma and erythrocytes from rats metabolized only 4-5% of the original compound in 3 hr. In cultured hepatocytes, 35% and 58.3%, respectively, of ET18-OMe was present after 6 and 24 hr as the metabolites 1-O-alkyl-2-O-methylglycerol (AMG), 1-O-alkyl-2-O-methylphosphatidic acid (AMPA), and stearyl alcohol (SA) (products of direct hydrolysis by phospholipases C and D and alkylhydrolase); phospholipids (phosphatidylcholine and phosphatidylethanolamine); and neutral lipids (products of secondary metabolism). In perfused rat liver, approximately 15% of the total radioactivity incorporated after 3 hr was distributed in metabolites as follows: 5.9% of AMPA, 5.0% of AMG, and 3.1% of SA. We conclude that the metabolism of ET18-OMe in normal tissues occurring through the same enzymes that metabolize natural lipids may partly explain the lack of effect in vivo. |
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Authors:
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A Magistrelli; P Villa; E Benfenati; E J Modest; M Salmona; M T Tacconi |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 23 ISSN: 0090-9556 ISO Abbreviation: Drug Metab. Dispos. Publication Date: 1995 Jan |
Date Detail:
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Created Date: 1995-05-23 Completed Date: 1995-05-23 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 113-8 Citation Subset: IM |
Affiliation:
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Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / blood, metabolism* Biotransformation Cells, Cultured Erythrocytes / metabolism Gas Chromatography-Mass Spectrometry Humans Liver / metabolism* Male Phospholipid Ethers / blood, metabolism* Rats Rats, Sprague-Dawley Tumor Cells, Cultured / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA 41314/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Phospholipid Ethers; 65492-82-2/edelfosine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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