共查询到20条相似文献,搜索用时 15 毫秒
1.
The effect of daily ingestion for 7 days of ethinyloestradiol (30 micrograms) plus DL-norgestrel [0.5 mg] (Eugynon-30) on the lipid composition of duodenal bile in 8 healthy young women was investigated from the fifth day after onset of menstrual bleeding. This treatment did not significantly affect the concentrations of cholesterol, phospholipid and total bile acids expressed as mmol/l, nor the mean molar percentage of phospholipid. However, the treatment caused a significant increase in the mean molar percentage of cholesterol which was accompanied by a significant decrease in the mean molar percentage of total bile acids. The cholesterol saturation index of the bile of 7 subjects was elevated after treatment while both serum cholesterol and testosterone were significantly reduced. The results show that administration to healthy young women, not previously exposed to oral contraceptives, with a low oestrogen-progestin preparation for only 7 days produces a more lithogenic bile, accompanied by a decrease in serum cholesterol and plasma testosterone concentrations. 相似文献
2.
J H Iser Paul N Maton Gerard M Murphy R Hermon Dowling 《BMJ (Clinical research ed.)》1978,1(6126):1509-1512
In most patients with radiolucent gall stones who were given chenodeoxycholic acid (CDCA) in doses of 13-15 mg/kg body weight/day the bile became unsaturated in cholesterol, and their gall stones dissolved. The patients whose stones did not dissolve were significantly heavier and fatter than the responders, which suggested that obese patients might be “resistant” to the effects of CDCA. To test this hypothesis, 32 consecutive patients presenting for medical treatment of gall stones had their ideal body weight (IBW) and estimated body fat mass calculated. The eight most obese and the eight least obese patients were then selected, and their fasting bile lipid responses to CDCA 13-15 mg/kg/day were measured. The very obese patients were also given larger doses, and any changes in bile lipid composition were studied in relation to subsequent gall-stone dissolution.Before treatment the obese patients had a higher mean biliary cholesterol saturation index than the non-obese patients, and this difference was maintained during treatment with the normal dose of CDCA: the bile in the obese patients remained supersaturated while that in the non-obese became unsaturated with cholesterol. When the obese patients were given larger doses of CDCA their bile ultimately became unsaturated in cholesterol. Gall stones dissolved partially or completely in five of the eight non-obese patients after 6-18 months of 13-15 mg CDCA/kg/day, but none of the obese patients showed any response after comparable periods of treatment with this standard dose. With increased doses and unsaturated bile, however, three of the obese patients showed partial gall-stone dissolution after 3-12 months'' treatment and one showed complete gall-stone dissolution after three years'' treatment.These results suggest that when giving CDCA to patients with gall stones, larger than normal doses (some 18-20 mg/kg/day) should be prescribed. Alternatively the lipid composition of the patients'' bile should be monitored by duodenal intubation and the CDCA dose increased until the bile becomes unsaturated in cholesterol. 相似文献
3.
Matsuzaki Y Bouscarel B Ikegami T Honda A Doy M Ceryak S Fukushima S Yoshida S Shoda J Tanaka N 《Biochimica et biophysica acta》2002,1588(2):139-148
The aim of this study was to explore the regulation of serum cholic acid (CA)/chenodeoxycholic acid (CDCA) ratio in cholestatic hamster induced by ligation of the common bile duct for 48 h. The serum concentration of total bile acids and CA/CDCA ratio were significantly elevated, and the serum proportion of unconjugated bile acids to total bile acids was reduced in the cholestatic hamster similar to that in patients with obstructive jaundice. The hepatic CA/CDCA ratio increased from 3.6 to 11.0 (P<0.05) along with a 2.9-fold elevation in CA concentration (P<0.05) while the CDCA level remained unchanged. The hepatic mRNA and protein level as well as microsomal activity of the cholesterol 7alpha-hydroxylase, 7alpha-hydroxy-4-cholesten-3-one 12alpha-hydroxylase and 5beta-cholestane-3alpha,7alpha,12alpha-triol 25-hydroxylase were not significantly affected in cholestatic hamsters. In contrast, the mitochondrial activity and enzyme mass of the sterol 27-hydroxylase were significantly reduced, while its mRNA levels remained normal in bile duct-ligated hamster. In conclusion, bile acid biosynthetic pathway via mitochondrial sterol 27-hydroxylase was preferentially inhibited in bile duct-ligated hamsters. The suppression of CYP27A1 is, at least in part, responsible for the relative decreased production of CDCA and increased CA/CDCA ratio in the liver, bile and serum of cholestatic hamsters. 相似文献
4.
A report on the effects of primary bile acid ingestion alone or in combination with plant sterols on serum cholesterol levels, biliary lipid secretion, and bile acid metabolism. Biliary bile acid and cholesterol secretion were measured in four patients with type IIa hypercholesterolemia before and after randomized treatment periods. During these periods either a bile acid mixture (cholic-chenodeoxycholic 2:1, a proportion similar to that endogenously synthesized in health), at a level of 20 mg/kg, or the same mixture plus sitosterols, 200 mg/kg, was fed. Serum cholesterol and the cholesterol saturation of fasting-state bile was also measured. Pretreatment biliary lipid secretion was within normal limits. Bile acid kinetic measurements were also recorded before treatment and showed that cholic acid synthesis was disproportionately decreased relative to that of chenodeoxycholic acid, a finding previously reported by others. Administration of the bile acid mixture increased biliary bile acid secretion in 3 of 4 patients, but did not influence biliary cholesterol secretion. The combination of sitosterol-bile acid, however, caused a relative decrease in cholesterol secretion in bile, and fasting-state bile became unsaturated in all patients. No change in fecal neutral sterol excretion occurred during the beta-sitosterol-bile acid regimen, suggesting that simultaneous bile acid feeding blocks the compensatory increase in cholesterol synthesis known to be induced by beta-sitosterol feeding in hypercholesterolemic patients. Serum cholesterol levels also fell modestly during the sitosterol-bile acid regimen, the decrease averaging 15%. We conclude that the abnormally low rate of bile acid synthesis in patients with type IIa hyperlipoproteinemia does not influence biliary lipid secretion; that increasing the input of the two primary bile acids into the enterohepatic circulation does not increase biliary cholesterol secretion or lower serum cholesterol levels in such patients; and that the usual increase in cholesterol synthesis induced by beta-sitosterol feeding does not occur if bile acids are administered simultaneously. 相似文献
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6.
Fifteen patients with gall stones who were taking chenodeoxycholic acid(CDCA) 15 mg/kg at bedtime participated in two separate experiments to investigate the effects of altering sterol intake on the cholesterol saturation index (SI) of fasting gall-bladder bile. In experiment I the 15 patients on an unrestricted diet had a SI of 0.87 +/- 0.04 (mean +/- SE of mean), which fell to 0.75 +/- 0.04 after one week in hospital on a diet of 100 mg cholesterol daily. In experiment II seven of the patients were given four different dietary regimens lasting one month each in random order as outpatients. On a diet of 600 mg of cholesterol daily the mean SI was 0.72 +/- 0.05, which fell to 0.67 +/- 0.05 when the patients were put on a 100 mg cholesterol diet. The addition of plant sterols (3 g daily) to both diets raised the mean SIs to 0.80 +/- 0.05 and 0.77 +/- 0.05 respectively. The percentage CDCA in bile was unaffected by alterations in the cholesterol and plant sterol intakes. We conclude that a low-cholesterol diet but not a high intake of plant sterols enhances the effect of CDCA in patients with gall stones. 相似文献
7.
Rotaviruses (group A rotaviruses) are the most important cause of severe gastroenteritis in infants and children worldwide. Currently, an antiviral drug is not available and information on therapeutic targets for antiviral development is limited for rotavirus infection. Previously, it was shown that lipid homeostasis is important in rotavirus replication. Since farnesoid X receptor (FXR) and its natural ligands bile acids (such as chenodeoxycholic acid [CDCA]) play major roles in cholesterol and lipid homeostasis, we examined the effects of bile acids and synthetic FXR agonists on rotavirus replication in association with cellular lipid levels. In a mouse model of rotavirus infection, effects of oral administration of CDCA on fecal rotavirus shedding were investigated. The results demonstrate the following. First, the intracellular contents of triglycerides were significantly increased by rotavirus infection. Second, CDCA, deoxycholic acid (DCA), and other synthetic FXR agonists, such as GW4064, significantly reduced rotavirus replication in cell culture in a dose-dependent manner. The reduction of virus replication correlated positively with activation of the FXR pathway and reduction of cellular triglyceride contents (r(2) = 0.95). Third, oral administration of CDCA significantly reduced fecal virus shedding in mice (P < 0.05). We conclude that bile acids and FXR agonists play important roles in the suppression of rotavirus replication. The inhibition mechanism is proposed to be the downregulation of lipid synthesis induced by rotavirus infection. 相似文献
8.
Jain AK Stoll B Burrin DG Holst JJ Moore DD 《American journal of physiology. Gastrointestinal and liver physiology》2012,302(2):G218-G224
Total parenteral nutrition (TPN) is essential for patients with impaired gut function but leads to parenteral nutrition-associated liver disease (PNALD). TPN disrupts the normal enterohepatic circulation of bile acids, and we hypothesized that it would decrease intestinal expression of the newly described metabolic hormone fibroblast growth factor-19 (FGF19) and also glucagon-like peptides-1 and -2 (GLP-1 and GLP-2). We tested the effects of restoring bile acids by treating a neonatal piglet PNALD model with chenodeoxycholic acid (CDCA). Neonatal pigs received enteral feeding (EN), TPN, or TPN + CDCA for 14 days, and responses were assessed by serum markers, histology, and levels of key regulatory peptides. Cholestasis and steatosis were demonstrated in the TPN group relative to EN controls by elevated levels of serum total and direct bilirubin and also bile acids and liver triglyceride (TG) content. CDCA treatment improved direct bilirubin levels by almost fourfold compared with the TPN group and also normalized serum bile acids and liver TG. FGF19, GLP-1, and GLP-2 were decreased in plasma of the TPN group compared with the EN group but were all induced by CDCA treatment. Intestinal mucosal growth marked by weight and villus/crypt ratio was significantly reduced in the TPN group compared with the EN group, and CDCA treatment increased both parameters. These results suggest that decreased circulating FGF19 during TPN may contribute to PNALD. Moreover, we show that enteral CDCA not only resolves PNALD but acts as a potent intestinal trophic agent and secretagogue for GLP-2. 相似文献
9.
We have already reported that peroxisomal beta-oxidation has an anabolic function, supplying acetyl-CoA for bile acid biosynthesis [H. Hayashi and A. Miwa, 1989, Arch. Biochem. Biophys. 274, 582-589]. The anabolic significance of peroxisomal beta-oxidation was further investigated in the present study by using clofibrate, a peroxisome proliferator, as an experimental tool. Clofibrate suppressed 3-hydroxymethylglutaryl-CoA reductase activity (the key enzyme of cholesterol synthesis) and enhanced fatty acyl-CoA oxidase activity (the rate-limiting enzyme of beta-oxidation). Rats were fed a chow containing 0.25% clofibrate for 2 weeks, and then a bile duct fistula was implanted. [1-14C]lignoceric acid, which is degraded exclusively by peroxisomal FAOS, was injected into the rats 24 h after the operation. By this time, the secondary bile acids and pooled cholesterol which would normally be secreted into the bile are considered to have been exhausted from the liver. Clofibrate significantly decreased the incorporations of radioactivity into biliary bile acid (40% of the control) and cholesterol (50%), but did not affect biliary lipid contents. [14C]Acetyl-CoA formed by peroxisomal beta-oxidation of [1-14C]lignoceric acid was preferentially utilized for syntheses of long-chain fatty acids and phospholipids rather than synthesis of cholesterol or triglyceride. The radioactivities incorporated into the former two lipids were increased 2-fold over the control by administration of clofibrate, while the incorporation into triglyceride was decreased to approximately half. In particular, the incorporation into phosphatidylethanolamine was increased as much as 3.5-fold over the control. The contents of these lipids in the liver were not affected by clofibrate. The results suggest that peroxisomal beta-oxidation plays an important role in the biosynthesis of functional lipids such as phospholipids (this work), in addition to bile acids and cholesterol (previous report) by supplying acetyl-CoA. 相似文献
10.
J P Shoenut 《Canadian journal of physiology and pharmacology》1986,64(8):1115-1118
Eighteen dogs were studied for 54 days. Rectal mucosal electrical potential difference (PD), gallbladder bile acids, cholesterol, and phospholipids were measured. It was shown that feeding chenodeoxycholic acid (CDCA) for 24 days in dosages of 15, 30, and 60 mg/kg of body weight, all depressed PD equally but significantly (P less than 0.05) in three groups of dogs compared with a control group. This depression was reversible 24 days after CDCA ingestion ceased in the two highest dosages. The low dose group was sacrificed after 24 days of CDCA feeding and the gallbladder bile was analyzed. CDCA and cholesterol were each significantly (P less than 0.05) elevated over control values in the gallbladder bile of these dogs. Phospholipids were not significantly changed. The PD, a reflection of Na+ -K+ ATPase activity, may be a useful indicator in maximizing dosages of CDCA in gallstone dissolution studies. 相似文献
11.
T S Low-Beer A C Wicks K W Heaton P Durrington J Yeates 《BMJ (Clinical research ed.)》1977,1(6076):1568-1570
We measured fasting serum and bile lipid concentrations at three intervals during the normal menstrual cycles of 11 healthy women not taking oral contraceptives. In nine of them cholesterol saturation of bile, and therefore presumably the risk of developing gall stones, was higher nine days after midcycle than at the end of menstruation. This change in bile cholesterol saturation was preceded by a significant fall in serum lipid concentrations: during the nine days after mid-cycle serum triglyceride and cholesterol concentrations fell in nine and eight of the 11 women respectively. Changes in the composition of serum and biliary lipids during the menstrual cycle are presumably due to a direct effect of sex hormones on the liver. 相似文献
12.
Nakahara M Fujii H Maloney PR Shimizu M Sato R 《The Journal of biological chemistry》2002,277(40):37229-37234
Recent studies have indicated that bile acids regulate the expression of several genes involved in bile acid and lipid metabolism as ligands for the farnesoid X receptor (FXR). We report here that bile acids are directly able to govern cholesterol metabolism by a novel mechanism. We show that chenodeoxycholic acid (CDCA) enhances low density lipoprotein (LDL) receptor gene expression in human cultured cell lines (HeLa, Hep G2, and Caco-2). The proteolytic activation of sterol regulatory element-binding protein-2 (SREBP-2), a major regulator for LDL receptor gene expression, is not affected by CDCA. Both deoxycholic acid and lithocholic acid as well as CDCA, but not ursodeoxycholic acid, increase the mRNA level for the LDL receptor, even when Hep G2 cells are cultured with 25-hydroxycholesterol, a potent suppressor of gene expression for the LDL receptor. Although it seems possible that FXR might be involved in genetic regulation, both reporter assays with a reporter gene containing the LDL receptor promoter as well as Northern blot analysis reveal that FXR is not involved in the process. On the other hand, inhibition of mitogen-activated protein (MAP) kinase activities, which are found to be induced by CDCA, abolishes the CDCA-mediated up-regulation of LDL receptor gene expression. We further demonstrate that CDCA stabilizes LDL receptor mRNA and that the MAP kinase inhibitors accelerate its turnover. Taken together, these results indicate that bile acids increase LDL uptake and the intracellular cholesterol levels through the activation of MAP kinase cascades in conjunction with a down-regulation of bile acid biosynthesis by FXR. This work opens up a new avenue for developing pharmaceutical interventions that lower plasma LDL by stabilizing LDL receptor mRNA. 相似文献
13.
Ki-Cheol Han Jung Hwan Kim Eunice EunKyeong Kim Eun Gyeong Yang 《Analytical biochemistry》2010,398(2):185-5146
Farnesoid X receptor (FXR) serves as a receptor for chenodeoxycholic acid (CDCA) and other bile acids, and it coordinates cholesterol and lipid metabolism. Because targeting the FXR-CDCA interaction might provide a way to regulate lipid homeostasis, we developed an FXR binding assay based on fluorescence polarization. Employing a fluorescently labeled CDCA (CDCA-F), we showed that CDCA-F selectively bound to the ligand binding domain of FXR (FXR-LBD) among nuclear receptors. The assay was then used for screening inhibitors against the FXR-CDCA interaction, thereby discovering four relatively potent inhibitors. The selected inhibitors were further studied for changes in intrinsic tryptophan fluorescence of FXR-LBD to gain structural insights into the interaction. Furthermore, transactivation effects of the inhibitors on the human bile salt excretory pump (BSEP) promoter were examined to reveal their cellular activities in the FXR-mediated pathway. Therefore, we demonstrated that the developed assay would offer an efficient primary screening tool for identifying FXR modulators. 相似文献
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15.
Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor 总被引:3,自引:0,他引:3
Pineda Torra I Claudel T Duval C Kosykh V Fruchart JC Staels B 《Molecular endocrinology (Baltimore, Md.)》2003,17(2):259-272
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor that controls lipid and glucose metabolism and exerts antiinflammatory activities. PPARalpha is also reported to influence bile acid formation and bile composition. Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that mediates the effects of bile acids on gene expression and plays a major role in bile acid and possibly also in lipid metabolism. Thus, both PPARalpha and FXR appear to act on common metabolic pathways. To determine the existence of a molecular cross-talk between these two nuclear receptors, the regulation of PPARalpha expression by bile acids was investigated. Incubation of human hepatoma HepG2 cells with the natural FXR ligand chenodeoxycholic acid (CDCA) as well as with the nonsteroidal FXR agonist GW4064 resulted in a significant induction of PPARalpha mRNA levels. In addition, hPPARalpha gene expression was up-regulated by taurocholic acid in human primary hepatocytes. Cotransfection of FXR/retinoid X receptor in the presence of CDCA led to up to a 3-fold induction of human PPARalpha promoter activity in HepG2 cells. Mutation analysis identified a FXR response element in the human PPARalpha promoter (alpha-FXR response element (alphaFXRE)] that mediates bile acid regulation of this promoter. FXR bound the alphaFXRE site as demonstrated by gel shift analysis, and CDCA specifically increased the activity of a heterologous promoter driven by four copies of the alphaFXRE. In contrast, neither the murine PPARalpha promoter, in which the alphaFXRE is not conserved, nor a mouse alphaFXRE-driven heterologous reporter, were responsive to CDCA treatment. Moreover, PPARalpha expression was not regulated in taurocholic acid-fed mice. Finally, induction of hPPARalpha mRNA levels by CDCA resulted in an enhanced induction of the expression of the PPARalpha target gene carnitine palmitoyltransferase I by PPARalpha ligands. In concert, these results demonstrate that bile acids stimulate PPARalpha expression in a species-specific manner via a FXRE located within the human PPARalpha promoter. These results provide molecular evidence for a cross-talk between the FXR and PPARalpha pathways in humans. 相似文献
16.
Bile acids are biosynthesized from cholesterol in hepatocytes and usually localize in the enterohepatic circulation system. This system is regulated by several transporters that are expressed in the liver and intestine. Organic solute transporter (OST) α/β, which is known as a bidirectional transporter for some organic anions, contributes to the transport of bile acids; however, the transport properties of individual bile acids are not well understood. In this study, we investigated the transport properties of five bile acids (cholic acid [CA], chenodeoxycholic acid [CDCA], deoxycholic acid [DCA], ursodeoxycholic acid [UDCA], and lithocholic acid [LCA]) together with their glycine and taurine conjugates mediated by OSTα/β. Of the unconjugated bile acids, CA, CDCA, DCA, and LCA were taken up by OSTαβ/MDCKII cells more rapidly than mock cells, but no significant increase in the uptake of UDCA was observed. On the contrary, all glycine- and taurine-conjugated bile acids showed a significant increase in the uptake by OSTαβ/MDCKII cells. Saturable OSTα/β-mediated transports of CDCA, DCA, glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), glycolithocholic acid (GLCA), taurochenodeoxycholic acid (TCDCA), and taurolithocholic acid (TLCA) were observed. The apparent Michaelis constants of CDCA, DCA, GCDCA, GDCA, GLCA, TCDCA, and TLCA for OSTα/β were 23.0 ± 4.0, 14.9 ± 1.9, 864.2 ± 80.7, 586.4 ± 43.2, 12.8 ± 0.5, 723.7 ± 4.8, and 23.9 ± 0.3 μM, respectively. However, the transport of other bile acids was not saturable. Our results indicate that OSTα/β has a low affinity but a high capacity for transporting bile acids. 相似文献
17.
Hofmann M Schumann C Zimmer G Henzel K Locher U Leuschner U 《Chemistry and physics of lipids》2001,110(2):908-171
Large unilamellar vesicles were prepared from phosphatidylcholine (PC), sphingomyelin (SM), cholesterol (Chol) and cardiolipin (CL) by an extrusion technique (LUVETs). Diffusion of the more hydrophobic lithocholic acid (LCA) and the less hydrophobic chenodeoxycholic acid (CDCA) was investigated by using the pyranine fluorescence method. Membrane permeability was studied by measuring the inclusion of carboxyfluoresceine (CF) into the lipid vesicles, and membrane fluidity was determined with diphenylhexatriene (DPH) and trimethylammonium-diphenylhexatriene (TMA-DPH). All results indicate that, CDCA compared to LCA, exhibits a significantly better penetration into vesicles containing SM. LCA penetrates better into vesicles containing cholesterol. Small amounts of CL influenced the diffusional properties of CDCA more than those of LCA. Since Lamcharfi et al. (1997a) Euro. Biophys. 25, 285-291 have observed differences in the conformational forms of CDCA and LCA in solution, it is suggested that the diffusion rate of bile acids through (model-)membranes is not only dependent on hydrophobicity, but also on bile acid di-(poly-)meric associations and on membrane-lipid composition. 相似文献
18.
The mechanisms of the changes in plasma lipids concentrations observed after beta-blockade were examined in 53 patients with hypertension receiving treatment with atenolol, metoprolol, propranolol, and oxprenolol in a randomised cross-over trial. Significant increases in mean plasma total and very-low-density lipoprotein (VLDL) triglyceride and reductions in high-density lipoprotein (HDL) cholesterol and free fatty acids concentrations wer observed with all four drugs, the increase in plasma triglyceride concentration being greatest after propranolol and oxprenolol. No significant changes were observed in total of LDL cholesterol concentrations, but HDL:LDL ratios and HDL cholesterol as a proportion of total cholesterol fell significantly. Thus plasma lipid concentrations should be monitored after three to six months of long-term treatment. Changes in triglyceride, HDL cholesterol and free fatty acid concentrations were associated with a highly significant reduction in clearance of soya oil (Intralipid) in 25 patients studied but were unrelated to changes in blood pressure. The fall in HDL cholesterol and rise in free fatty acid concentrations were significantly less in those with initially reduced HDL cholesterol or raised free fatty acid concentrations respectively. It is proposed that unopposed alpha stimulation inhibits lipoprotein lipase with a subsequent rise in plasma triglyceride and fall in HDL cholesterol concentration. Analysis of the relation between pretreatment concentrations and subsequent changes suggests that excessive alpha stimulation may impair production of HDL cholesterol in those with low HDL cholesterol concentrations before treatment. Subtle catecholamine-mediated changes in plasma lipid concentrations might provide a mechanism for the relation between stress and the development of cardiovascular events. 相似文献
19.
S Phornchirasilp S T Patel J M Hanson H A Newman D T Witiak D R Feller 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1989,191(2):139-146
4-Chlorophenol (4-CP) is an identified trace contaminant in commercial clofibrate preparations and the pharmacologic effects of 4-CP have not yet been widely established. We have examined the dose-dependent effects of oral 4-CP and clofibrate administration on selected hepatic parameters and on serum glucose, cholesterol, and triglyceride concentrations in male rats. 4-CP treatment (0.00125-0.08 mmol/kg, twice a day) of rats for 2 weeks increased hepatic microsomal protein (20-30%) and cytochrome P-450 (20-190%) contents without changing liver/body weight ratios. Both 4-CP (0.0025 mmol/kg body wt, twice a day) and CPIB (0.4 mmol/kg body wt, twice a day) treatment to rats for 2 weeks caused significant elevations in microsomal cytochrome P-450 content and in the maximal activities of ethylmorphine, aminopyrine, and benzphetamine N-demethylase, but not in the activity of zoxazolamine 6-hydroxylase. With the same dose of 4-CP, time-dependent increases in hepatic microsomal protein, cytochrome P-450, and the activity of benzphetamine N-demethylase were observed for a 4-week period, and the induction of hepatic microsomal benzphetamine N-demethylase activity by 4-CP was associated with an increased enzyme synthesis. 4-CP treatment produced a marked morphologic change in liver cell ultrastructure, including a proliferation of mitochondria and endoplasmic reticulum at lower 4-CP doses. A clustering of intracellular organelles (mitochondria and endoplasmic reticulum) and a foamy cytoplasm were seen at doses greater than 0.01 mmol/kg, twice a day for 2 weeks, and at 0.0025 mmol/kg, twice a day for greater than 4 weeks. The effects of 4-CP and clofibrate on fasting blood glucose and fasting serum lipid levels were also monitored throughout an 8-week period. Both 4-CP (0.005 mmol/kg body wt, twice a day) and clofibrate (0.2 mmol/kg body wt, twice a day) produced significant elevations in fasting serum glucose levels, but this dosage of 4-CP did not alter serum lipid and lipoprotein parameters, whereas clofibrate significantly reduced serum total cholesterol and high density lipoprotein cholesterol levels. These results lead us to conclude that 4-CP does not contribute to the antilipidemic effects of clofibrate. 相似文献
20.