Rosuvastatin suppresses the liver microsomal CYP2C11 and CYP2C6 expression in male Wistar rats.

The aim was to investigate whether rosuvastatin affect rat cytochrome P450 (CYP) 2C11 and CYP2C6. CYP2C11 and CYP2C6 are considered as counterparts of human CYP2C9, which metabolizes many drugs including S-warfarin, diclofenac or ibuprofen. The male Wistar rats were fed standard laboratory diet (STD) or high cholesterol diet (HCD, 1% of cholesterol, 10% of lard fat) for 21 days. Rosuvastatin administration in STD (0.03% w/w) resulted in decreased mRNA expression of CYP2C11 as well as of CYP2C6 (here significant) and in a significant decrease of the respective protein expression as well as of the enzyme activity of both CYP2C forms. When rosuvastatin was administered in the HCD, the mRNA expression of both CYP2C forms was significantly lowered; the protein and activity parameters did not show significant changes. These results suggest that CYP2C11 as well as CYP2C6 expression and activity are negatively affected by rosuvastatin and may be modulated by high cholesterol high fat diet. Therefore, it should be taken into consideration that drugs metabolized by CYP2C9 in human could interact with rosuvastatin, as it has been already suggested for warfarin (rosuvastatin has increased its anticoagulant effect in human), and for telmisartan, sildenafil and glimepiride.

The influence of rosuvastatin on liver microsomal CYP2C6 in hereditary hypertriglyceridemic rat.

OBJECTIVES: The aim of this study was to investigate whether rosuvastatin affects expression and activity of rat CYP2C6. This cytochrome P450 is considered to be a counterpart of human CYP2C9, which metabolizes many drugs, including diclofenac, ibuprofen or warfarin. DESIGN: Male hereditary hypertriglyceridemic (HHTg) rats were fed standard laboratory diet (STD) or high cholesterol diet (HCD: STD + 1% of cholesterol w/w + 10% of lard fat w/w) for 21 days. A third group of rats were fed high a cholesterol diet with rosuvastatin added (0.03% w/w). Expression of CYP2C6 was measured in liver samples using real-time PCR (mRNA level) and Western blotting (protein level). Formation of diclofenac metabolites (typical enzyme activity of CYP2C6) was analyzed using HPLC with UV detection. RESULTS: Administration of rosuvastatin to HHTg rats resulted in significantly increased mRNA expression and enzyme activity in HCD-fed animals; changes of CYP2C6 protein were non-significant. These results suggest that CYP2C6 expression and activity are positively affected by rosuvastatin in hereditary hypertriglyceridemic rats after intake of HCD. CONCLUSION: The results presented open the possibility that in humans, rosuvastatin may affect the metabolism of many drugs by influencing expression and activity of CYP2C6 (counterpart of human CYP2C9). Further studies are needed to elucidate the effects of this statin on CYP2C9 in humans.

Fenofibrate-induced decrease of expression of CYP2C11 and CYP2C6 in rat.

This short communication is aimed to investigate whether the widely used hypolipidemic drug fenofibrate affects CYP2C11 and CYP2C6 in rats, both counterparts of human CYP2C9, known to metabolise many drugs including S-warfarin and largely used non-steroidal antiinflammatory drugs such as ibuprofen, diclofenac and others. The effects of fenofibrate on the expression of rat liver CYP2C11 and CYP2C6 were studied in both healthy Wistar rats and hereditary hypertriglyceridemic rats. Both strains of rats were fed on diet containing fenofibrate (0.1% w/w) for 20 days. Fenofibrate highly significantly suppressed the expression of mRNA of CYP2C11 and less that of CYP2C6 in liver microsomes of both rat strains; this effect was associated with a corresponding decrease in protein levels. The results indicate that the combination of fenofibrate with drugs metabolised by CYP2C9 in humans should be taken with caution as it may lead, for example, to the potentiation of warfarin effects. This type of drug interaction has been observed previously and the results presented here could contribute to the explanation of their mechanism.

The influence of maca (Lepidium meyenii) on antioxidant status, lipid and glucose metabolism in rat.

This work focused on the effect of Maca on lipid, anti-oxidative, and glucose parameters in hereditary hypertriglyceridemic (HHTg) rat. Maca (1%) was administred to rats as a part of a high-sucrose diet (HSD) for 2 weeks. Rosiglitazone (0.02%) was used as a positive control. Maca significantly decreased the levels of VLDL (very low density lipoproteins), LDL (low density lipoproteins), and total cholesterol, and also the level of TAG (triacylglycerols) in the plasma, VLDL, and liver. Maca, as well as rosiglitazone, significantly improved glucose tolerance, as the decrease of AUC (area under the curve) of glucose showed, and lowered levels of glucose in blood. The activity of SOD (superoxide dismutase) in the liver, the GPX (glutathione peroxidase) in the blood, and the level of GSH (glutathione) in liver increased in all cases significantly. Results demonstrate that maca seems to be promising for a positive influence on chronic human diseases (characterized by atherogenous lipoprotein profile, aggravated antioxidative status, and impaired glucose tolerance), and their prevention.

Effect of silymarin and its polyphenolic fraction on cholesterol absorption in rats.

This study evaluated the influence of silymarin (SM) and polyphenolic fraction (PF) of silymarin on cholesterol absorption in rats fed on high cholesterol diet (HCD). HCD induced a remarkable increase in hepatic, plasma, VLDL and LDL cholesterol, a decrease in HDL cholesterol and an elevation in triacylglycerol (TAG) levels in plasma, VLDL and in the liver. SM and PF were administered as dietary supplements (1.0%) in HCD for 18 days. Intestinal cholesterol absorption was measured by dual-isotope plasma ratio method, which calculates percent of cholesterol absorption from the ratio of two labelled cholesterol doses, one given intragastrically (14C) and one intravenously (3H). Silymarin and PF significantly reduced cholesterol absorption in rats fed on HCD and caused significant decreases in plasma and VLDL cholesterol and content of cholesterol and TAG in the liver. The level of HDL cholesterol was significantly increased after silymarin, but not after administration of PF. The levels of TAG in plasma and VLDL were not affected by either silymarin or PF. These results suggest that the inhibition of cholesterol absorption caused by silymarin and its polyphenolic fraction could be a mechanism contributing to the positive changes in plasma cholesterol lipoprotein profile and in lipid content in liver.

Phenolics-rich extracts from Silybum marianum and Prunella vulgaris reduce a high-sucrose diet induced oxidative stress in hereditary hypertriglyceridemic rats.

The study tested the effects of phenolics-rich extracts from the plants Silybum marianum (silymarin) and Prunella vulgaris (PVE) on blood and liver antioxidant status and lipoprotein metabolism. Hereditary hypertriglyceridemic rats fed on standard diet (STD) or high-sucrose diet (HSD, 70cal% of sucrose) for two weeks were used. HSD doubled plasma and liver triacylglycerol (TAG) and increased plasma VLDL-TAG and VLDL-cholesterol compared to STD. Administration of silymarin or PVE as 1% dietary supplements in HSD did not influence lipid levels in plasma or liver, but both extracts caused decrease in plasma VLDL-cholesterol levels. HSD-induced oxidative stress was manifested in increased TBARS and conjugated dienes (CD) content, decreased GSH levels and glutathione peroxidase (GPX) activity in blood and liver. In blood the activity of superoxide dismutase (SOD) decreased, whereas in liver the activity of catalase increased after HSD. Feeding on HSD containing phenolics-rich extracts resulted in reduction of TBARS and CD content and in increase of blood GPX activity and elevated GSH content in liver. Besides, silymarin increased the activity of SOD and level of GSH in blood. Catalase activity in blood or liver was not influenced by the presence of plant extracts in the diet. These results indicate that silymarin and PVE improve antioxidant status in blood and liver and positively affect plasma lipoprotein profile in an experimental model of dietary induced hypertriglyceridemia.

Plasma lipoproteins in transport of silibinin, an antioxidant flavonolignan from Silybum marianum.

To assess the role of plasma lipoproteins in the transport of silibinin, an antioxidant flavonolignan, (125)I-labelled silibinin ((125)I-SB) administered perorally to the rat was used. The plasma (125)I-SB derived radioactivity was distributed among plasma lipoproteins according to their lipophilicity (TAG-rich lipoproteins 30-40% > LDL 15% > HDL 5%), and in the fraction of d > 1.215 containing albumin and other proteins a minority amount of radioactivity was found. Administration of (125)I-SB in a complex with phosphatidylcholine resulted in proportionally higher radioactivities in all fractions as well as in tissues. Dietary olive oil had a slightly decreasing effect on plasma concentrations of silibinin measured by HPLC as well as on (125)I-SB derived radioactivity in plasma and liver. In the TAG-rich lipoprotein fraction and HDL no effects of olive oil on the levels of (125)I-SB derived radioactivities were observed, however, at a 30 min interval the levels of (125)I-SB derived radioactivity in LDL and the heart were significantly decreased in the olive oil group. These results suggest that (i) silibinin is not resorbed by the chylomicron pathway, and (ii) the endogenous lipoprotein pathway VLDL --> LDL may play a role in the transport of silibinin from the liver to the extrahepatic tissues concurrently facilitating the lipoprotein antioxidant influence of silibinin.

Effects of polyphenolic fraction of silymarin on lipoprotein profile in rats fed cholesterol-rich diets.

To study the influence of polymerised polyphenolics (PP), a fraction of silymarin (SM), on lipids and oxidant status, rats were fed high-cholesterol (1%), high-fat (10%) diets containing either lard fat (LFD) rich in saturated/monounsaturated fatty acids, or currant oil (COD) rich in polyunsaturated fatty acids. PP and SM were administered as dietary supplements (0.1-0.5-1.0%) for 3 weeks. PP (1%) decreased cholesterol (C) in VLDL (from 0.72+/-0.08 mmol l(-1) in LFD control to 0.35+/-0.07 mmol l(-1), P<0.01, and from 0.33+/-0.05 mmol l(-1) in COD control to 0.09+/-0.02 mmol l(-1), P<0.001), and increased HDL-C/VLDL-C ratio, however, without effect on the total plasma C and LDL-C. Liver C content (LFD 19.32+/-1.50 micromol g(-1), COD 18.64+/-2.13 micromol g(-1), N.S.) decreased after PP (1%) to 12.24+/-0.76 micromol g(-1), P<0.01, and 8.78+/-0.95 micromol g(-1), P<0.001, respectively. Triacylglycerols (TAG) in plasma and VLDL decreased after PP in the LFD group only, which displayed higher TAG levels than the COD group. Likewise, LFD caused a higher liver TAG content than did COD (31.16+/-3.00 micromol g(-1) versus 17.31+/-1.48 micromol g(-1), P<0.01), and PP (1%) decreased liver TAG only in rats fed LFD (19.55+/-2.43 micromol g(-1), P<0.02). Blood glutathione (GSH) increased after PP (1%) in the LFD group from 0.97+/-0.11 to 1.54+/-0.19 mmol l(-1) (P<0.05) and in the COD group from 0.58+/-0.15 to 1.23+/-0.10 mmol l(-1) (P<0.01), while liver GSH and plasma TBARS did not change. On principle, effects of PP were dose-dependent and parallel to SM. These results suggest that the polyphenolic fraction of SM positively modifies lipoprotein profile, counteracts the development of fatty liver and ameliorates an antioxidant status in circulation.