NMR spectroscopic analyses of liver phosphatidylcholine and phosphatidylethanolamine biosynthesis in rats exposed to peroxisome proliferators - A class of nongenotoxic hepatocarcinogens

Peroxisome proliferators (PPs) are commercial/industrial chemicals that dis play tumor promoter activity in rodents. The mechanism is not completely un derstood, and our ability to predict tumorigenicity a priori is even less d eveloped. Wy-14,643, perfluorooctanoic acid (PFOA), and di(2-ethylhexyl)pht halate (DEHP) are strong, moderate, and weak tumor promoters, respectively, while perfluorodecanoic acid (PFDA) lacks promoter activity. This investig ation examined the effects of these PPs on the biosyntheses of phosphatidyl choline (PtdC) and phosphatidylethanolamine (PtdE) in rat liver. After expo sure to PPs, rats were administered [1-C-13]choline + [2-C-13]ethanolamine and liver extracts were analyzed by P-31 and C-13 NMR. The ratio of choline -derived to ethanolamine-derived phospholipids, R-c/e, was significantly af fected by all PPs (p < 0.05), R-c/e values were in the order Wy-14,643 > PF OA > DEHP > control > PFDA. The amounts of PtdC derived via the CDP-choline pathway versus PtdE-N-methyltransferase (PEMT) activity was 71 vs 29% in c ontrols. This distribution was significantly affected by treatments with Wy 14,643 (95 vs 5%), DEHP (87 vs 13%), and PFDA (39 vs 61%) (p < 0.02), Data suggest that Wy-14,643, PFOA, and DEHP cause a preference for choline and t he CDP-choline pathway for biosynthesis of PtdC. Additionally, Wy-14,643 an d DEHP inhibited the PEMT pathway. In contrast, PFDA-treated rats showed a preference for ethanolamine, and PtdC was predominately synthesized through the PEMT pathway. These data corroborate studies by Vance and co-workers w hich suggest that the pathways for PtdC biosynthesis are important for hepa tocarcinogenesis. Further studies to evaluate the potential of these measur ements as a biomarker for PP-associated tumorigenesis is warranted. (C) 200 0 Academic Press.