Effect of bile duct ligation on bile acid and cholesterol metabolism in rats

The effects of bile duct ligation on bile acid and cholesterol metabolism were examined in male Wistar strain rats. Quantitative and qualitative changes of bile acids and cholesterol in serum and urine occurred; beta-muricholic acid predominantly increased in serum and urine and the ratio of urinary cholic acid and beta-muricholic acid changed from about 5:3 on day 1 to about 1:8 on day 5 under biliary obstruction. The form of the increased urinary bile acids was mainly taurine-conjugated and partly sulfated. Under conditions of bile duct ligation on day 5, 14C-labeled 3 beta-hydroxy-5-cholenoic, lithocholic, and chenodeoxycholic acids were intragastrically administered to the rats after pretreatment with antibiotics and the metabolites of these three acids were investigated. 3 beta-Hydroxy-5-cholenoic acid was most efficiently converted to beta-muricholic acid. The present study strongly suggested the presence of an alternative metabolic pathway induced by bile duct ligation, which caused the change in composition of urinary bile acids, and especially the marked increase in beta-muricholic acid formation. A possible alternative pathway for bile acid biosynthesis under biliary obstruction in rats is postulated.     

Effect of ethanol on cholesterol and bile acid metabolism

Ethanol feeding increased significantly levels of hepatic esterified cholesterol and serum free and esterified cholesterol in rats. Incorporation of intraperitoneally administered [(14)C]acetate into cholesterol was significantly increased. Labeling of cholesterol was also enhanced in liver slices from animals pretreated with ethanol and incubated with [(14)C]-acetate. Ethanol consumption prolonged the half-excretion time of labeled cholic or chenodeoxycholic acids, increased slightly the pool size, and decreased daily excretion. By contrast, supplementation of the diet with cholesterol shortened the half-excretion time, did not modify pool size, and increased daily excretion. When ethanol and cholesterol feeding were combined, the effects of ethanol prevailed and there was suppression of the adaptive changes in bile acid metabolism induced by cholesterol feeding. There was also a greater accumulation of esterified cholesterol in the liver than that produced by cholesterol alone, ethanol administration alone, or the summation of both effects. Thus, cholesterol accumulation produced by ethanol feeding is associated with both enhanced cholesterogenesis and decreased bile acid excretion. Both mechanisms may play a role, but the latter is probably predominant in these studies in which cholesterol accumulation was markedly enhanced by the addition of cholesterol to the ethanol-containing diet.     

Differential effects of dimethyl sulfoxide on human platelet aggregation and arachidonic acid metabolism

DMSO inhibited human platelet aggregation induced by ADP, AA, PAF, or collagen in a concentration-related manner, in vitro. DMSO was a more effective inhibitor for aggregation induced by ADP and collagen than PAF or AA. However, in vivo experiments on rabbits showed that DMSO did not protect rabbits against death from pulmonary platelet thrombosis induced by AA. On the other hand, DMSO (1-30% v/v) had no effect on thromboxane production by platelets incubated with [14C]AA. Moreover, DMSO stimulated PGE2 production by bovine seminal vesicle PG synthase. DMSO also stimulated the production of 12-HETE but inhibited the production of tri-HETE produced via lipoxygenase pathway. Since lipoxygenase products play an important role in inflammation, our data suggest that the anti-inflammatory effects of DMSO are probably not mediated via its action on AA metabolism.     

Effects of chronic glucagon administration on cholesterol and bile acid metabolism

Male adult Wistar rats received daily, at 9 a.m. and 5 p.m., 10 micrograms of Zn-protamine glucagon for 21 days by subcutaneous injections. The blood glucose level was not significantly modified. Cholesterol and triacylglycerol levels were decreased by 40 and 70% in plasma but not in the liver. The rates of cholesterol turnover processes were determined in vivo with an isotope balance method. Internal secretion of cholesterol (13.8 +/- 0.5 mg/day per rat in control rats and 22.4 +/- 0.9 mg/day per rat in glucagon-treated rats) and cholesterol transformation into bile acids were strikingly increased by chronic administration of glucagon. Biliary secretion rates of bile acids measured by a wash-out method were increased by 139%, while the intestinal bile acid pool was not changed. The enterohepatic cycle number was increased from five per day in control rats to nine per day in glucagon-treated rats. An increased turnover rate of the exchangeable cholesterol would explain the hypocholesterolemic effect of glucagon.     

Role of CYP27A in cholesterol and bile acid metabolism

The CYP27A gene encodes a mitochondrial cytochrome P450 enzyme, sterol 27-hydroxylase, that is expressed in many different tissues and plays an important role in cholesterol and bile acid metabolism. In humans, CYP27A deficiency leads to cerebrotendinous xanthomatosis. To gain insight into the roles of CYP27A in the regulation of cholesterol and bile acid metabolism, cyp27A gene knockout heterozygous, homozygous, and wild-type littermate mice were studied. In contrast to homozygotes, heterozygotes had increased body weight and were mildly hypercholesterolemic, with increased numbers of lipoprotein particles in the low density lipoprotein size range. Cyp7A expression was not increased in heterozygotes but was in homozygotes, suggesting that parts of the homozygous phenotype are secondary to increased cyp7A expression and activity. Homozygotes exhibited pronounced hepatomegaly and dysregulation in hepatic cholesterol, bile acid, and fatty acid metabolism. Hepatic cholesterol synthesis and synthesis of bile acid intermediates were increased; however, side chain cleavage was impaired, leading to decreased bile salt concentrations in gallbladder bile. Expression of Na-taurocholate cotransporting polypeptide, the major sinusoidal bile salt transporter, was increased, and that of bile salt export pump, the major canalicular bile salt transporter, was decreased. Gender played a modifying role in the homozygous response to cyp27A deficiency, with females being generally more severely affected. Thus, both cyp27A genotype and gender affected the regulation of hepatic bile acid, cholesterol, and fatty acid metabolism.     

Development of bile acid metabolism: effect of glucocorticoids on bile acid metabolism in the neonatal rat

The objective of this study was to examine the effect of glucocorticoid treatment in early neonatal life on plasma cholesterol and hepatic cholesterol 7 alpha-hydroxylase (CH-7A), the rate-limiting enzyme of bile acid biosynthesis from cholesterol, measured at weaning (Postnatal Day 20). Neonatal rat pups were injected subcutaneously with 5 micrograms of dexamethasone (DEXA) or vehicle (CON) for 5 days between Postnatal Days 4 and 8. On Postnatal Day 20, the animals were used for various studies. DEXA-treated pups weighed significantly less (P less than 0.001) than controls. Even though DEXA-treated animals had significantly smaller livers (P less than 0.001), microsomal protein per gram of liver was significantly greater (P less than 0.005) in the DEXA-treated animals. CH-7A activity (pmole/mg . min) was significantly lower (P less than 0.005) in the DEXA-treated animals (CON (4) 19.4 +/- 2.8; DEXA (4) 5.0 +/- 1.0). Plasma cholesterol (mg/100 ml) was significantly greater (P less than 0.005) in the DEXA-treated animals (CON (5) 179 +/- 7; DEXA (4) 223 +/- 5), a finding consistent with lower CH-7A activity in this group. Taurocholate absorption by in situ ileal loops in anesthetized rats was significantly greater in the DEXA-treated animals in agreement with the in vitro observations of Little and Lester. The basis for the reduced CH-7A activity in DEXA-treated pups is not known. It may be due in part to a new steady state in the enterohepatic circulation of bile acids resulting from a glucocorticoid-induced enhanced conservation of bile acids.     

The effect of dimethyl sulfoxide on the enantioselectivity in the pig liver esterase catalyzed hydrolysis of dialkylated propanedioic acid dimethyl esters

The effect of dimethyl sulfoxide (DMSO) on the enantioselectivity in the pig liver esterase (EC 3.1.1.1) catalyzed hydrolysis of dialkylated propanedioic acid diesters was studied. Increasing concentrations of DMSO increased the ratio of the (R)-enantiomers of the produced monoesters. This effect was not due to the change in pH_app caused by the solvent. The reaction rate was lowered to one-tenth of the rate without DMSO when the DMSO concentration was increased to 50%.     

The absorption, metabolism and excretion of dimethyl sulfoxide by rhesus monkeys

The absorption and excretion of dimethyl sulfoxide (DMSO) were studied in Rhesus monkeys (Macaca mulatta) given daily oral doses of 3 gms DMSO/kg B.W. for 14 days. DMSO and its major metabolite, dimethyl sulfone (DMSO2), were measured in serum, urine and feces by gas-liquid chromatography. DMSO was absorbed rapidly, reached a steady state blood level after 1 day and then was cleared from blood within 72 hrs after ending treatment. Serum DMSO declined in a linear fashion on semilogarithmic coordinates as described by second order kinetics. It had a half-life of 16 hrs. DMSO2 appeared in blood within 2 hrs and reached a steady state concentration after 4 days of treatment. DMSO2 was cleared from blood about 120 hrs after DMSO administration was stopped. Its half-life in blood was calculated to be 38 hrs. Urinary excretion of unmetabolized DMSO and DMSO2 accounted for about 60% and 16%, respectively, of the total ingested dose. Neither DMSO nor DMSO2 was detected in fecal samples. However, when added to fecal samples, DMSO was degraded rapidly. Although dimethyl sulfide (DMS) was not measured, some DMSO was metabolized to this compound because of the particular sweetness of breath of the monkeys. We conclude that the absorption of DMSO by monkeys is similar to that for humans, but that its conversion to DMSO2 and urinary elimination are more rapid in monkeys.     

The mean conformation of N-acetylamino acid N'-methylamides in dimethyl sulfoxide solution

The mean conformation of a series of N-acetylamino acid N'-methylamides in dimethyl sulfoxide (DMSO) was determined by 1H-NMR and 13C-NMR methods.The series investigated consisted of derivatives of DL-Ala, DL-Asn, Gln, His, DL-Ile, DL-Leu, Met, DL-Pro, DL-Phe, Ser, Thr, Trp, Tyr, DL-Val, DL-Nva, and dl-Nle. It was found that the conformational equilibria in DMSO are dominated by C5 and C7eq forms.The amounts of these forms in the equibbria were found to be roughly proportional to the Boltzmann probabilities for the occurrence of a definite form, as calculated theoretically by Vasquez et al.(Macromolecules 16 (1983) 1043).Exceptions to this rule were DL-Pro and, to a lesser extent, Ser, Asn and Trp derivatives.     

Antistress effect of dimethyl sulfoxide in the rat

Administration of scavenger of hydroxyl radicals--dimethylsulfoxide (1 g/kg intraperitoneally, daily for 3 weeks) did not lead to any significant changes in animals behaviour in the open field and in visceral functions (arterial pressure, respiratory rate, heart rate) but prevented shifts of these characteristics caused by chronic 3-week emotional-pain stress. In rats injected with dimethylsulfoxide, an increase was observed of superoxide dismutase activity in the brain and blood serum. Molecular mechanisms are discussed of antistress action of dimethylsulfoxide (scavenge of hydroxyl radicals, activation of superoxide dismutase) and possible role of hydroxyl radicals in realization of damaging action of stress on the organism.     

Effect of mevinolin and glycyrrhizinic acid on cholesterol and bile acid metabolism in cultured rabbit hepatocytes]

A comparison of effects of two hypocholesterolemic drugs--mevinolin and glycyrrhizinic acid, on cholesterol and bile acid metabolism in cultured rabbit hepatocytes has been carried out. The following parameters have been determined: i) cholesterol synthesis from [2-14C]acetate; ii) bile acid production from newly synthesized and [4-14C]-labeled HDL2 cholesterol, and, iii) total cholesterol efflux into the incubation medium Mevinolin (0.5 microgram/ml) inhibited [2-14C] acetate incorporation into cholesterol by more than 90%. Conversely, glycyrrhizinic acid did not influence cholesterol synthesis even when used at high (100 micrograms/ml) concentrations but stimulated the conversion of endogenous (by 37%) and exogenous (by 18%) cholesterol into bile acids and increased, in addition, the proportion of bile acids in the total sterol pool released from hepatocytes into the incubation medium. At the same time, mevinolin used at 0.5 microgram/ml decreased the bile acid production by endogenous (by 27%) and exogenous (by 40%) cholesterol. The data obtained suggest that glycyrrhizinic acid exerts hypocholesterolemic action by stimulation of cholesterol conversion into bile acids without any effect on cholesterol synthesis. As for mevinolin, it has a cholesterol-suppressing effect via a mechanism of cholesterol synthesis inhibition only.     

Effect of portacaval anastomosis on the activities of hepatic enzymes related to cholesterol and bile acid metabolism in rats.

1. The effect of a portacaval anastomosis on the activities of hepatic enzymes related to cholesterol metabolism was investigated in rats. 2. Portacaval anastomosis led to a fall in body weight and liver weight/body weight ratio, and to a rise in the activities of hydroxymethylglutaryl-CoA reductase and cholesterol 7alpha-hydroxylase per g of liver. The net effect was to maintain a normal activity of both enzymes per 100 g of rat. Diurnal rhythm in the activities of both enzymes was maintained after portacaval anastomosis. 3. The rate of excretion of total bile acids, per 100 g of rat, in bile fistula rats was not significantly decreased by portacaval anastomosis.     

The effect of molybdenum on ascorbic acid metabolism in rats

1. The effect of dietary molybdenum on the growth rate and also on ascorbic acid metabolism in rats was studied. An excess of dietary molybdenum resulted in growth retardation and loss of weight. Tolerance to molybdenum was affected by the nature of the molybdenum salt administered. 2. Molybdenum ingestion altered certain aspects of ascorbic acid metabolism in rats. The conversion of d-glucuronolactone into l-ascorbic acid in vitro and the oxidative breakdown of l-ascorbic acid by liver enzymes decreased with high molybdenum intakes. The activity of liver uronolactonase was slightly inhibited. The activities of l-gulonate dehydrogenase and l-gulonate decarboxylase were not affected appreciably. 3. Molybdenum supplementation of the control diet resulted in an increase in ascorbic acid content of spleen and adrenal gland, and in a marked decrease in the urinary excretion of ascorbic acid and glucuronic acid. The implications of these findings are discussed.