Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, on quantitative and qualitative changes in lipoprotein metabolism was investigated in 18 patients (group I, 10 with primary kidney disease and group II, 8 with diabetic nephropathy) with nephrotic syndrome. Nephrotic patients exhibited severe hyperlipidemia (serum cholesterol 390 +/- 17 mg/dl and triglyceride 335 +/- 42 mg/dl; mean +/- SEM) and had significantly higher lipoprotein (a) [Lp(a)] levels (54 +/- 12 mg/dl; median 31 mg/dl, p < 0.01) compared with 20 healthy subjects (mean 12 +/- 1.8 mg/dl; median 7 mg/dl). Fifty-six percent of the patients and 15% of the controls had values greater than 30 mg/dl. Treatment with simvastatin in increasing doses over a period of three months (13 patients received 40 mg/day and 5 patients 20 mg/day at the end of the third month) reduced LDL-cholesterol in both groups of patients (35% and 54%) as well as apolipoprotein B (apoB) (31% and 46%) significantly, but Lp(a) levels were not influenced (57 +/- 21 vs 59 +/- 20 and 50 +/- 14 vs 53 +/- 16 mg/dl, respectively). On the other hand a complex change in lipoprotein composition occurred. The ratio of LDL apoB/LDL cholesterol-ester increased significantly (0.75 +/- 0.03 to 0.84 +/- 0.03 and 0.80 +/- 0.03 to 1.02 +/- 0.1, respectively) and cholesterol concentration in VLDL (64 +/- 16 to 39 +/- 7 and 74 +/- 18 to 55 +/- 74 mg/dl, respectively) was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of simvastatin on lipoprotein (a) and lipoprotein composition in patients with nephrotic syndrome. 818 55

Androsterone sulfate (Andros-S) is the most abundant 5 alpha-reduced androgen metabolite in serum. To determine whether this steroid could serve as a marker of 5 alpha-reductase activity, we developed a specific RIA, using tritiated Andros-S to assess procedural losses. Baseline serum Andros-S levels (mumol/L; mean +/- SEM) in 14 hirsute women (3.0 +/- 0.4) were not reduced by ovarian suppression with leuprolide (3.0 +/- 0.3), but were decreased by 79% with combined ovarian and adrenal suppression with leuprolide and dexamethasone. The mean Andros-S level in polycystic ovarian syndrome (3.2 +/- 0.4) and in idiopathic hirsutism (3.5 +/- 0.5) was not significantly different from levels in normal women (3.0 +/- 0.5), but were significantly greater than levels in obese women (1.7 +/- 0.3; P < 0.05). The serum concentrations of Andros-S were about 10-fold greater than those of androsterone glucuronide and 100-fold greater than those of androstanediol glucuronide. Serum Andros-S concentrations correlated strongly with dehydroepiandrosterone sulfate (R = 0.59; P < 0.001) and to a lesser degree with androstanediol glucuronide and androsterone glucuronide (R = 0.28 and 0.49, respectively). There was a weak correlation with androstenedione levels and the androstenedione response to ACTH (R = 0.38 and 0.34, respectively), and no significant correlation with serum testosterone (R = 0.19). The ratio of any of the 5 alpha-reduced products (Andros-S, androstanediol glucuronide, and androsterone glucuronide) to precursors (androstenedione and testosterone) was not increased in hirsute women, suggesting that these women did not have a generalized increase in 5 alpha-reductase activity. In conclusion, these results confirm that Andros-S is the most abundant 5 alpha-reduced androgen metabolite in serum. It is primarily, if not exclusively, of adrenal origin in hirsute women. The fact that its levels were not elevated in hirsutism, although those of other adrenal androgens and androgen metabolites (androstanediol glucuronide and androsterone glucuronide) were, suggests that variations in sulfotransferase activity or metabolic clearance of Andros-S may be important determinants of serum Andros-S levels. Although Andros-S may be a marker of systemic 5 alpha-reductase activity, there was no evidence of a generalized increase in 5 alpha-reductase activity in hirsute women. Andros-S is therefore not recommended as a marker of either adrenal androgen production or of hirsutism.
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PMID:Androsterone sulfate: physiology and clinical significance in hirsute women. 838 Jun 2

Steroid hormone production within the gonads and adrenals requires a continuous supply of cholesterol derived from de novo synthesis within the gland and from uptake of circulating plasma lipoproteins. Steroid hormone secretion was prospectively studied over 24 months in 64 hypercholesterolemic subjects (group I, aged 52 +/- 1 years [mean +/- SEM], 61% male) participating in a randomized double-blind clinical trial of pravastatin (20 to 80 mg daily), a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, compared with patients taking cholestyramine or other lipid-lowering drugs (group II). Attempts were made in both groups to maintain serum low-density lipoprotein cholesterol (LDL-C) levels between the 25th and 50th percentile for age and gender. At 24 months, serum LDL-C level decreased by 42% +/- 3% in group I and 44% +/- 1% in group II (P < .001 v baseline, NS between groups). Basal secretion of cortisol, aldosterone, and dehydroepiandrostenedione sulfate (DHEA-S) was maintained throughout the study. However, the serum DHEA-S secretory response to Cortrosyn (Organon, West Orange, NJ) diminished in both treatment groups at 6 and 12 months (P < .05). In men, basal serum testosterone levels and the testosterone response to human chorionic gonadotropin (HCG) did not change. There was some diminution of sperm motility noted in both treatment groups at 6 and 12 months in the subset of men undergoing semen analysis (n = 14, P < .05). In conclusion, pravastatin had no significant effect on steroid metabolism. Changes noted in DHEA-S were not specific for pravastatin, suggesting that this impairment is related to lipid-lowering effects.
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PMID:Long-term endocrine function in hypercholesterolemic patients treated with pravastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. 841 67

It is unknown whether the clearance of atherogenic chylomicron remnants and the postprandial lipoprotein metabolism in general can be improved by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in subjects with familial combined hyperlipidemia (FCH). Therefore, the postprandial chylomicron remnant clearance was studied in nine normolipidemic untreated controls and seven FCH patients before and after treatment with simvastatin using an oral vitamin A-fat load (24 hours, 50 g/m2). Treatment with simvastatin reduced plasma cholesterol level by 16% (mean +/- SEM, 8.1 +/- 0.8 v 6.8 +/- 0.8 mmol/L; P < .05) and plasma apolipoprotein (apo) B level by 19% (1.6 +/- 0.2 v 1.3 +/- 0.2 g/L; P < .05). Plasma apo E level (89.6 +/- 21.0 mg/L) was reduced by 29% (63.5 +/- 14.1 mg/L; P < .05). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels did not change; consequently, the reductions seen had been due to a decrease in very-low-density lipoprotein (VLDL) levels. Fasting plasma triglyceride (30% reduction) and plasma apo C-II (31% reduction) levels did not change significantly. Mean postheparin plasma lipoprotein lipase (LPL) activity increased by 13% after treatment (90.4 +/- 19.8 v 102.6 +/- 20.3 mU/mL; P < .05), but hepatic lipase (HL) activity was not altered. The clearance of chylomicrons (Sf > 1,000), expressed as the area under the 24-hour retinyl palmitate curve, did not change with simvastatin (52.8 +/- 12.9 v 51.8 +/- 13.4 h.mg-1/L).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Simvastatin improves chylomicron remnant removal in familial combined hyperlipidemia without changing chylomicron conversion. 848 74

The relationship between lipoprotein(a) [Lp(a)] and metabolism of triglyceride-rich lipoproteins (TRL) was studied in 58 untreated patients with familial combined hyperlipidemia (FCH) from eight different kindreds, 17 spouse controls, and 17 unrelated controls. Lp(a) plasma concentrations were not significantly different between FCH subjects (343 +/- 61 mg/L, mean +/- SEM) and controls (249 +/- 52 mg/L). In FCH, log-transformed Lp(a) levels correlated positively with postheparin lipoprotein lipase ([LPL] r = .61, P = .0002) and hepatic lipase ([HL] r = .46, P = .008) activities and total plasma cholesterol level (r = .30, P = .03). In controls, Lp(a) correlated with LPL (r = .50, P = .04) and total plasma cholesterol level (r = .51, P = .003). In eight FCH patients, treatment with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin resulted in significantly increased mean LPL activities and plasma Lp(a) concentrations. In three of these FCH patients, repeated measurements during 1 year demonstrated that changes in Lp(a) concentrations were paralleled by similar changes in LPL activity, but not HL activity. The observed correlation between postheparin plasma lipolytic activities and Lp(a) plasma concentrations suggests a connection between the metabolism of TRL and Lp(a).
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PMID:Lipoprotein(a) plasma concentrations associated with lipolytic activities in eight kindreds with familial combined hyperlipidemia and normolipidemic subjects. 851 May 21

Although the effects of 3-hydroxy, 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and bile acid sequestrants on bile lipid composition have been studied separately, no data are available on combination therapy of these drugs. Moreover, the effects of prolonged (four weeks) administration of these drugs on gall bladder motility, an important determinant of cholesterol gall stone formation, have not been studied so far. A prospective study was therefore performed with eight patients who had hypercholesterolaemia (age 53 (5) (SEM), body mass index 27.4 (1.1) kg m-2, low density lipoprotein cholesterol 5.9 (0.3) mmol/l). They received treatment during three periods of four weeks with simvastatin 20 mg/day, cholestyramine 4 g twice daily, and a combination of both in random order, each treatment period separated by a two week wash out period. Before treatment and after each treatment period, postprandial gall bladder motility was studied with ultrasound, followed by duodenal bile sampling. Serum cholesterol decreased in all subjects in any treatment period illustrating good compliance. Molar percentages in duodenal bile of cholesterol, phospholipids, and bile salts were unchanged during simvastatin and cholestyramine treatment. During combined therapy percentage bile salts was lower (72.5 (2.9)% v 77.8 (1.7)% at baseline, p < 0.05) whereas phospholipids were higher (21.2 (2.4)% v 16.4 (1.3)% at baseline, p < 0.05). As a result cholesterol saturation index (CSI) did not change in any treatment period. No cholesterol crystals were detected in any bile sample, taken at baseline and after each treatment period. Bile salt hydrophobicity index during cholestyramine (0.19 (0.02)) and combined treatment (0.22 (0.01)) decreased strongly compared with baseline (0.34 (0.01), p < 0.001, p < 0.01, respectively), resulting from increased proportions of glycocholate (59.4 (3.9)% (cholestyramine), 55.6 (2.4)% (combination), and 28.2 (2.2) (baseline), p < 0.001)) and decreased proportions of deoxycholic acid and chenodeoxycholic acid. Fasting gall bladder volume was increased during simvastatin (28.7 (2.8) ml) v baseline (23.2 (2.3) ml, p < 0.01) whereas, residual volume did not differ (5.7 (0.9) ml (simvastatin) v 5.9 (0.7) (baseline). During cholestyramine and combined treatment, no significant differences in gall bladder motility were seen. In conclusion, this study suggests that HMG-CoA reductase inhibitors alone and combined with cholestyramine do not affect major determinants of cholesterol gall stone formation, for example, CSI and gall bladder emptying. In addition cholestyramine alone and combined with simvastatin leads to a strong decrease of bile salt hydrophobicity, which may be beneficial in the prevention of nucleation of cholesterol crystals.
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PMID:Effects of simvastatin and cholestyramine on bile lipid composition and gall bladder motility in patients with hypercholesterolaemia. 854 41

Finasteride, a 5 alpha-reductase inhibitor, decreases prostate size and improves symptoms in men with benign prostatic hyperplasia. However, little is known about prostate histopathology in men taking finasteride. To determine the mechanism by which finasteride reduces prostate size, tissue was collected at the time of prostatectomy from men taking either no medication (n = 10) or 5 mg finasteride daily for 6-18 days (n = 6; group 1), 23-73 days (n = 5; group 2), or 3 months to 4 yr (n = 5; group 3). To assess whether finasteride causes epithelial atrophy, morphometric measurement of epithelial cell and duct width was used. The mean epithelial cell width in control prostates (mean +/- SEM, 21 +/- 0.7 microns) decreased with duration of treatment to 19 +/- 1 microns in group 1, 15 +/- 2 microns in group 2, and 8 +/- 0.3 microns in group 3. Mean duct width decreased from 135 +/- 6 microns in the control prostates to 128 +/- 10 microns in group 1, 103 +/- 3 microns in group 2, and 63 +/- 6 microns in group 3. To assess whether prostate cell death was occurring, sections were in situ end labeled for DNA breaks and immunostained for tissue transglutaminase (tTG), a marker of apoptosis (programmed cell death). The percentage of epithelial cells staining for DNA breaks was 0.4 +/- 0.2 in control prostates, 2.8 +/- 0.9 in group 1, 1.7 +/- 0.5 in group 2, and 0.7 +/- 0.3 microns in group 3. Anti-tTG staining of epithelial cells was graded on a scale of 0-4. In control prostates, 3 +/- 1% of the ducts were grade 3 or 4 (> 50% of epithelial cells staining). In finasteride-treated prostates, 2 +/- 2% of the prostates in group 1, 13 +/- 4% of the prostates in group 2, and 0.5 +/- 0.5% of the prostates in group 3 were grade 3-4. These results indicate that a progressive decrease in epithelial cell size and function occurs during the first several months in the prostates of men treated with finasteride. The staining for DNA breaks and the tTG staining also indicate that an increased rate of apoptosis is occurring transiently in these prostates. We conclude that finasteride causes prostate involution through a combination of atrophy and cell death.
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PMID:Evidence for atrophy and apoptosis in the prostates of men given finasteride. 863 9

Of 17 patients with idiopathic membranous nephropathy (IMN) and nephrotic syndrome, 9 were allocated to treatment with simvastatin (an HMG CoA-reductase inhibitor) and low cholesterol diet, and 8 to diet alone. At entry, the treatment and control groups did not differ in mean serum creatinines, chromium-labelled EDTA clearances, urinary protein/creatinine ratios, serum albumins, and lipid profiles. The mean follow up period (+/- SEM) in the treated group was 19.3 (+/- 4.4) months compared with 16.6 (+/- 5.9) months in the control group. At the end of the trial the fall in chromium-labelled EDTA clearances was similar (-1.27 versus -1.28 mls/min/months/1.73 m2) in the treatment and control groups respectively. The mean (+/- SEM) total and LDL-cholesterol had gone from 10.5 (+/- 0.94) and 8.02 (+/- 1) mmol/l to 5.2 (+/- 0.49) and 3.47 (+/- 0.44) respectively in the treated patients. Additionally the mean (+/- SEM) albumin and urinary protein/creatinine ratio went from 25.6 (+/- 2.4) gm/l and 0.52 (+/- 0.09) gm/mmol to 45.5 (+/- 2.8) and 0.13 (+/- 0.04) respectively. There was little change in total and LDL-cholesterol; albumin and urinary protein/creatinine ratio in the control group. This study supports the observation that lowering serum cholesterol in the nephrotic syndrome reduces proteinuria and increases serum albumin levels. No difference in the rate of decline in renal function could be demonstrated.
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PMID:A prospective clinical trial comparing the treatment of idiopathic membranous nephropathy and nephrotic syndrome with simvastatin and diet, versus diet alone. 890 5

Supersaturation of bile with cholesterol is a prerequisite of the development of gallstones. With the intention to study the integrated response of enzymes regulating hepatic cholesterol metabolism during gallstone formation we used an established model for the induction of cholesterol gallstone disease in mice. Ten mice were fed on a lithogenic diet containing 10 g cholesterol/kg and 5 g cholic acid/kg for 8 weeks and were compared with ten mice fed on a standard pellet diet. Cholesterol crystals or gallstones developed in 90% of gallbladders in treated mice. The lithogenic diet had an inhibitory effect on the rate-limiting enzyme of cholesterol biosynthesis, hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.88) activity, 39.6 (SEM 2.8) v. 171.0 (SEM 47.3) pmol/min per mg protein. Cholesterol 7 alpha-hydroxylase (EC 1.14.13.17) activity, regulating bile acid synthesis, was decreased by 80%, and this was assumed to be due to cholic acid in the diet. The cholesterol-enriched diet also induced a tenfold increase in cholesterol esterification rate in the liver, i.e. acyl-CoA:cholesterol acyl transferase (ACAT; EC 2.3.1.26) activity. The total, as well as esterified, cholesterol contents of liver homogenates were significantly higher in cholesterol- and cholic acid-treated mice and correlated well with the ACAT activity (rs 0.72 (P < 0.005), and rs 0.68 (P < 0.01) respectively). A significantly higher ACAT activity was obtained in mice given cholesterol and cholic acid even when the enzyme was saturated with exogenous cholesterol, thus indicating an increased amount of the enzyme. The formation of gallstones is dependent on a delicate balance between lithogenic factors (increased absorption of cholesterol and reduced secretion of bile acids) and defence mechanisms (decreased synthesis and increased esterification of cholesterol). In the specific animal model studied here the two defence mechanisms cannot compensate for the increased absorption of cholesterol and the reduced synthesis of bile acids.
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PMID:Lithogenic diet and gallstone formation in mice: integrated response of activities of regulatory enzymes in hepatic cholesterol metabolism. 895 9

A single 300-mg i.p. injection of poloxamer 407 (P-407, also called Pluronic F-127) in rats produces a marked hypercholesterolemia for a minimum of 96 h. The purpose of this investigation was to determine mechanisms by which P-407 causes hypercholesterolemia. The enzyme targeted for investigation is the rate-limiting enzyme in cholesterolgenesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Injection of P-407 in fasted rats resulted in a significant (p < 0.05) elevation in plasma cholesterol (61.2 +/- 4.2 mg/dl) as soon as 1 h after injection compared with sham-injected controls (50.1 +/- 3.7 mg/dl). Plasma cholesterol (CHO) 24 h after injection of P-407 was 449 +/- 57 mg/dl, with the fastest rate of accumulation occurring from 1 to 12 h (approximately 16.6 mg/dl/h). Over the concentration range of 0-5 mM, P-407 did not appear significantly to affect the activity of HMG-CoA reductase in vitro. However, the enzymatic activity assayed in microsomal fractions isolated from the livers of P-407-injected rats reached a maximum of 262 +/- 42.6 pmol mevalonate/min/mg approximately 15 h after injection, with a subsequent decline to control activity (94.1 +/- 8.7 pmol/min/mg) at approximately 40 h after injection. At 48 h after injection of P-407, the activity of HMG-CoA reductase significantly (p < 0.05) decreased below control values with a mean activity of 9.4 +/- 1.2 pmol/min/mg. The CHO concentrations in hepatic tissue were significantly (p < 0.01) increased at 2 h (3.26 +/- 0.19 mg/g) and 4 h (3.75 +/- 0.38 mg/g) and significantly (p < .01) reduced at 15 h (1.56 +/- 0.19 mg/g) after injection of P-407 compared with tissue CHO concentrations determined in control animals (2.65 +/- 0.18 mg/g). However, the hepatic CHO content appeared to return to control values by 24 h (mean +/- SEM, 2.61 +/- 0.08 mg/g) after injection. These data suggest that the activity of HMG-CoA reductase is regulated by some indirect mechanism(s) after injection of P-407 in rats.
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PMID:Effect of poloxamer 407 on the activity of microsomal 3-hydroxy-3-methylglutaryl CoA reductase in rats. 921 98


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