Hypocholesterolemic and antioxidant properties of 3-(4-hydroxyl)propanoic acid derivatives in high-cholesterol fed rats.
ABSTRACT The purpose of the present study was to evaluate the in vivo efficacy of two cinnamic acid synthetic derivatives (allyl 3-[4-hydroxyphenyl]propanoate; HPP304, 1-naphthyl-methyl 3-[4-hydroxyphenyl]propanoate; HPP305) in high-cholesterol fed rats and compare their actions to that of cinnamic acid. Cinnamic acid and its synthetic derivatives were supplemented with a high-cholesterol diet for 42 days at a dose of 0.135 mmol/100g of diet. The supplementation of HPP304 and HPP305 significantly lowered cholesterol and triglyceride levels in the plasma and liver with a simultaneous increase in the HDL-cholesterol concentration, whereas cinnamic acid only lowered the plasma cholesterol concentration. Cinnamic acid lowered hepatic HMG-CoA reductase activity in high-cholesterol fed rats, however, its synthetic derivatives (HPP304 and HPP305) did not affect HMG-CoA reductase activity compared to the control group. Instead, the HPP304 and HPP305 supplements significantly lowered hepatic acyl coenzyme A:cholesterol acyltransferase activity and increased the fecal bile acid. The SOD activity of the erythrocytes and liver was not different between the groups, however, the activities of CAT and GSH-Px, and the level of GSH in the erythrocytes were significantly higher in the HPP304 and HPP305 groups than in the control group. On the other hand, the activities of CAT and GSH-Px, and the level of malondialdehyde in the liver were significantly lower in the HPP304 and HPP305 groups. The antioxidant activities of these cinnamic acid synthetic derivatives were similar to the cinnamic acid in the high-cholesterol fed rats. In addition, HPP304 and HPP305 lowered amniotransferase activity in the plasma. These results suggest that two cinnamic acid synthetic derivatives (HPP304 and HPP305) exert lipid-lowering action and antioxidant properties without hepatotoxicity in high-cholesterol fed rats.
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ABSTRACT: This article reviews our current understanding of the mechanisms of low-density lipoprotein (LDL) oxidation and the potential role of oxidized lipoproteins in atherosclerosis. Studies in hypercholesterolemic animal models indicate that oxidation of LDL is likely to play an important role in atherogenesis. Epidemiological investigations further suggest that the dietary intake of antioxidants is inversely associated with the risk of vascular disease, suggesting that oxidized LDL may be important in human atherosclerosis. By activating inflammatory events, oxidized lipoproteins may contribute to all stages of the atherosclerotic process. Lipoprotein oxidation is promoted by several different systems in vitro, including free and protein-bound metal ions, thiols, reactive oxygen intermediates, lipoxygenase, peroxynitrite, and myeloperoxidase. Intracellular proteins that bind iron or regulate iron metabolism might also play an important role. The physiologically relevant pathways have yet to be identified, however. We assess recent findings on the effects of antioxidants in vivo and suggest potential strategies for inhibiting oxidation in the vessel wall.Free Radical Biology and Medicine 02/1996; 20(5):707-27. · 5.27 Impact Factor
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ABSTRACT: Cholesterol is a 27-carbon steroid that is an essential component of the cell membrane, the immediate precursor of steroid hormones, the substrate for the formation of bile acids, and is required for the assembly of very low density lipoprotein in the liver. Because as much as two-thirds of total body cholesterol in patients is of endogenous origin, an effective means to control cholesterogenesis may occur by inhibition of its biosynthesis. Cholesterol is biosynthesized in a series of more than 25 separate enzymatic reactions that initially involve the formation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). Early attempts to pharmacologically block cholesterol synthesis focused only on steps later in the biosynthetic pathway and resulted in compounds with unacceptable toxicity. Recent research had identified that HMG CoA reductase is a key rate-limiting enzyme in this pathway and is responsible for the conversion of HMG CoA to mevalonate. Additional research with fungal metabolites identified a series of compounds with potent inhibiting properties for this target enzyme, from which lovastatin was selected for clinical development. A reduction in cholesterol synthesis by lovastatin has been subsequently confirmed in cell culture, animal studies and in humans. A resultant decrease in circulating total and low-density lipoprotein (LDL) cholesterol has also been demonstrated in animals and humans. Because hepatic LDL receptors are the major mechanism of LDL clearance from the circulation, further animal research has confirmed that these declines in cholesterol are accompanied by an increase in hepatic LDL receptor activity. Lovastatin effectively diminishes endogenous cholesterol synthesis providing useful therapeutic properties for patients with hypercholesterolemia.The American Journal of Cardiology 12/1988; 62(15):10J-15J. · 3.21 Impact Factor
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ABSTRACT: The antioxidant activity of the major phenols derived from hydroxycinnamic acid (caffeic, ferulic, and p-coumaric acids) on in vitro LDL oxidation was screened, using Cu2+ as catalyst. The presence of the second phenolic hydroxy group enhanced the inhibitory effect of these compounds. In fact, at 5 microM concentration, only caffeic acid completely protected LDL from modification as measured as conjugated dienes formation and apo B-100 fragmentation, also preserving alpha-tocopherol. The effect of caffeic acid in inhibiting LDL oxidative modification induced by three different oxidant systems was tested. Using both Cu2+ and 2,2'-azobis (2-amidinopropane)-hydrochloride (AAPH), the inhibitory effect of caffeic acid was dose-dependent. Yet, the better protection was achieved in the metal-ion dependent system. Also the murine macrophages-mediated LDL oxidation was efficiently inhibited by 5 microM caffeic acid. UV-VIS spectra of caffeic acid incubated with cupric ions show the formation of a caffeic acid:copper complex, responsible for a transient chelating activity. This mechanism, coupled with its free radical scavenging property, accounts for the higher inhibitory activity exhibited by caffeic in Cu(2+)-catalyzed reaction.Free Radical Biology and Medicine 12/1995; 19(5):541-52. · 5.27 Impact Factor