Hypolipidemic drugs are inhibitors of phosphatidylcholine synthesis.

Parthasarathy, S.; Kritchevsky, David; Baumann, Wolfgang J.

doi:10.1073/pnas.79.22.6890

Cited by 13 publications

(5 citation statements)

References 50 publications

(63 reference statements)

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“…Control animals were infused with the vehicle solution without the drug. [24]. MDL 29350 completely inhibited the rat microsomal PE N-methyltransferase activity at a concentration of 5 UM (Fig.…”

Section: Resultsmentioning

confidence: 78%

Synthesis of phosphatidylethanolamine and ethanolamine plasmalogen by the CDP-ethanolamine and decarboxylase pathways in rat heart, kidney and liver

Arthur

Page

1991

Biochemical Journal

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Studies with mammalian cell lines have led to suggestions that mammalian tissues may derive all of their phosphatidylethanolamine (PE) from the decarboxylation of phosphatidylserine (PS), and also that the physiological significance of the CDP-ethanolamine pathway was the synthesis of ethanolamine plasmalogen. We have therefore investigated the biosynthesis of PE and ethanolamine plasmalogen via the CDP-ethanolamine and decarboxylation pathways in vivo in three rat tissues (heart, kidney and liver), which differ in ethanolamine plasmalogen content. In all three tissues [14C]ethanolamine was incorporated into both PE and ethanolamine plasmalogen, whereas [3H]serine was incorporated into only PS and PE fractions. When [14C]ethanolamine was introduced into the animals, the specific radioactivity of ethanolamine plasmalogen in the kidney was always greater than that of the PE fraction; in the heart the specific radioactivity of the ethanolamine plasmalogen fraction was similar to that of the PE fraction, whereas in the liver the specific radioactivity of the PE fraction was always greater than that of the ethanolamine plasmalogen fraction. The results obtained in this study indicate that: (1) the CDP-ethanolamine pathway is utilized for the synthesis of both PE and ethanolamine plasmalogen in all three tissues; (2) the decarboxylation pathway is utilized solely for the synthesis of PE; (3) serine plasmalogens are not formed by base-exchange reactions; (4) the relative utilization of the CDP-ethanolamine pathway for the synthesis of PE and ethanolamine plasmalogen varies among tissues. Our studies also revealed that the hypolipidaemic drug MDL 29350 is a potent inhibitor of PE N-methyltransferase activity in vitro and in vivo.

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Section: Resultsmentioning

confidence: 78%

Synthesis of phosphatidylethanolamine and ethanolamine plasmalogen by the CDP-ethanolamine and decarboxylase pathways in rat heart, kidney and liver

Arthur

Page

1991

Biochemical Journal

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“…In addition to increases in the content of PtdCho and PtdEth observed for all treatments (Figure 4), our data show that PFDA and PFOA also caused an increase in the mole percentage of PtdCho, while Wy-14,643 increased the percentage of PtdEth (Table 1). Contrary to these findings, Parthasarathy et al (55) have shown that several hypolipidemic drugs, including clofibrate, inhibited PtdCho synthesis in rat liver microsomes. Thorne and co-workers (17) reported that Wy-14,643, DEHP, and clofibrate reduced the synthesis of PtdEth in human fibroblasts; however, all but clofibrate enhanced the synthesis of PtdCho.…”

Section: Discussionmentioning

confidence: 78%

“…Previous studies from our laboratory and others have provided evidence that PPs significantly affect liver phospholipid metabolism ( − ). The effects of various PPs on the accumulation or degradation of individual phospholipids appear to be varied.…”

Section: Introductionmentioning

confidence: 92%

Effects of Peroxisome Proliferators on Rat Liver Phospholipids: Sphingomyelin Degradation May Be Involved in Hepatotoxic Mechanism of Perfluorodecanoic Acid

Adinehzadeh

Reo

1998

Chem. Res. Toxicol.

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Perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), clofibrate, di(2-ethylhexyl)phthalate (DEHP), and Wy-14,643 represent a class of compounds known as peroxisome proliferators (PPs). Such compounds induce biogenesis of liver peroxisomes and cause a varying degree of hepatotoxicity and carcinogenesis in rodents. We examined the effects of these PPs on rat hepatic lipids and phospholipid profiles using phosphorus-31 NMR spectroscopy. All PPs caused a 25-57% increase in hepatic phospholipid content, while all but clofibrate increased the total lipid content by 26-156%. Treatments also influenced the composition of liver phospholipids. Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEth) contents were significantly increased in all treatment groups. Most notably, PFDA caused the largest increase in PtdCho and PtdEth content (ca. 70%), while PFOA and Wy-14,643 were the only test compounds that influenced the PtdCho:PtdEth ratio. PFDA also caused an ca. 30% decrease in sphingomyelin (SphM) from 24 to 120 h postdose. SphM is a key lipid in signal transduction processes involved in apoptosis. Hydrolysis of SphM can be mediated through the action of tumor necrosis factor (TNF-alpha). We measured the TNF-alpha concentrations in rat sera at 24 h post-PFDA-exposure and found an 8-fold increase relative to vehicle-treated controls. These data demonstrate that an increase in the serum TNF-alpha level correlates with the time frame for the observed reduction in hepatic SphM. PFOA, a structurally similar compound, had no effect on hepatic SphM content, nor did it affect the serum TNF-alpha concentration. These effects may be related to differences in the tumorigenicity associated with these compounds. We postulate that PFDA activates the SphM signal transduction pathway via the release of TNF-alpha. This then stimulates cytotoxic responses and processes of apoptosis and may suppress cell proliferative and mitogenic responses.

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“…This may account for the increased PC levels in PBC patients [39]. In fact, several hypolipidaemic drugs act by reducing the hepatic synthesis of cholesterol and PC [40] whose serum levels decline concomitantly. Therefore, the increased content of PC in RBC ghosts of PBC patients is most likely the consequence of the increased hepatic cholesterol synthesis.…”

Section: Discussionmentioning

confidence: 99%

Structural and oxidative modifications of erythrocyte ghosts in patients with primary biliary cirrhosis: relation with the disease stage and effect of bile acid treatment

Grattagliano

Giudetti

Grattagliano

et al. 2003

Eur J Clin Investigation

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Hypolipidemic drugs are inhibitors of phosphatidylcholine synthesis.

Cited by 13 publications

References 50 publications

Synthesis of phosphatidylethanolamine and ethanolamine plasmalogen by the CDP-ethanolamine and decarboxylase pathways in rat heart, kidney and liver

Synthesis of phosphatidylethanolamine and ethanolamine plasmalogen by the CDP-ethanolamine and decarboxylase pathways in rat heart, kidney and liver

Effects of Peroxisome Proliferators on Rat Liver Phospholipids: Sphingomyelin Degradation May Be Involved in Hepatotoxic Mechanism of Perfluorodecanoic Acid

Structural and oxidative modifications of erythrocyte ghosts in patients with primary biliary cirrhosis: relation with the disease stage and effect of bile acid treatment

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