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.
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.
Magistrelli
A
A
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Villa
P
P
Benfenati
E
E
Modest
E J
EJ
Salmona
M
M
Tacconi
M T
MT
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism*; D001711:Biotransformation; D002478:Cells, Cultured; D004912:Erythrocytes / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D010742:Phospholipid Ethers / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured / Q000378:metabolism
D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; C026659:edelfosine