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

A. Magistrelli, P. Villa, E. Benfenati, E. J. Modest, M. Salmona, M. T. Tacconi

Research output: Contribution to journalArticlepeer-review

Abstract

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°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, ~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.

Original languageEnglish
Pages (from-to)113-118
Number of pages6
JournalDrug Metabolism and Disposition
Volume23
Issue number1
Publication statusPublished - 1995

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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