Search PubMed⌕ Search

Biomedical subjects

W C Duane

Publications and source records attributed to W C Duane.

At least 19 recordsLinked to original sources
PubMed1992

Measurement of bile acid synthesis in man by release of 14CO2 from [26-14C]cholesterol: comparison to isotope dilution and assessment of optimum cholesterol specific activity.

Bile acid synthesis can be measured as release of 14CO2 from [26-14C]cholesterol divided by cholesterol specific activity, but this method has not been validated in human subjects. We made twelve comparisons of this CO2 method to standard isotope dilution in six normal subjects and found a mean discrepancy of 6%. Linear regression analysis of one value with respect to the other revealed a correlation coefficient of 0.83 (P less than 0.01), a Y-intercept close to zero (-4.98) and a slope close to 1 (1.06), suggesting good correspondence between the two methods. To assess the potential for error arising from use of serum cholesterol to estimate specific activity of cholesterol used for bile acid synthesis, we compared synthesis measured using serum free cholesterol specific activity to that measured using bile cholesterol specific activity, which is known to be near isotopic equilibrium with the precursor pool used for bile acid synthesis. Synthesis calculated in these two ways differed by less than 10%. The data indicate that the CO2 method using either serum or bile cholesterol specific activity provides a valid estimate of bile acid synthesis in man.

Bile Acids and Salts↗
PubMed1992

Lack of benefit of ursodeoxycholic acid in drug-induced cholestasis in the rat.

The administration of ursodeoxycholic acid (UDCA) has been reported to improve cholestasis in patients with primary biliary cirrhosis or sclerosing cholangitis. In the present study, we tested the hypothesis that UDCA similarly might reduce cholestasis induced by drugs. Rats were treated with three different drugs reported to induce cholestasis: 17 alpha-ethynylestradiol, alpha-napthylisothiocyanate, and cyclosporine A. UDCA administration (0.4.g/day-1.k-1 before and during administration of the cholestatic drug) did not improve survival, food intake, or serum indicators of cholestasis in any of these three animal models of cholestasis. To the extent that drug-induced cholestasis in rats mimics the human situation, we conclude that UDCA probably will not be beneficial in drug-induced cholestasis in humans.

1-Naphthylisothiocyanate↗
PubMed1992

Thyroid hormone differentially augments biliary sterol secretion in the rat. I. The isolated-perfused liver model.

Thyroid hormone lowers serum cholesterol and alters sterol metabolic processes. This laboratory has previously reported increased biliary lipid secretion as an early effect of triiodothyronine (T3) in the rat. To evaluate whether the bile lipid action of T3 is a primary or secondary effect, the isolated-perfused rat liver model was used. Red blood cells in lipid-free buffer were used to perfuse livers of euthyroid and methimazole-hypothyroid rats, as well as hypothyroid rats given T3 at intervals before perfusion. Bile flow was maintained by taurocholate perfusion. Hypothyroid rats had elevated pre-perfusion serum cholesterol compared to euthyroid (107 +/- 4 vs. 65 +/- 2 mg/dl) and decreased biliary cholesterol (0.016 +/- 0.001 vs. 0.031 +/- 0.004 mumol/g liver/h) secretion. Serum cholesterol decreased to euthyroid levels by 18 h after T3, an effect that was prevented by bile duct ligation. Bile cholesterol secretion doubled by 18 h, and reached levels twice euthyroid by 42 h, while phospholipid secretion doubled to levels just above euthyroid. The fourfold increase in biliary cholesterol secretion occurred with lipid-free perfusion and unchanging bile acid uptake or output. It occurred without a fall in hepatic lipoprotein cholesterol secretion. Blockade of cholesterol synthesis with lovastatin failed to alter T3-augmented bile cholesterol secretion. We conclude that T3 induces biliary cholesterol secretion concomitantly with the fall in serum cholesterol. This augmented biliary secretion did not appear to depend upon lipoprotein uptake, increased bile acid transport, or cholesterol synthesis. It did not occur at the expense of hepatic lipoprotein secretion. Facilitated biliary lipid secretion may be a primary effect of T3.

Animals↗
PubMed1992

Separation of bile vesicles and micelles by gel filtration chromatography: the importance of the intermicellar bile salt concentration.

Micelles and vesicles coexist in native bile. Mixed micelles are composed of bile salt, phospholipid, and cholesterol. Micellar bile salt is in equilibrium with the aqueous phase bile salt (intermicellar bile salt), and mixed micelles can be converted to cholesterol-phospholipid vesicles by depletion of bile salt. To determine the amount of cholesterol carried in vesicles and micelles, these two populations must be separated without altering the relative proportion of each. Based on the size difference between micelles and vesicles, gel filtration chromatography has been used to accomplish this separation. We reasoned that to maintain the proportion of micelles and vesicles in bile, the column must be equilibrated and eluted with buffer containing the intermicellar bile salt concentration (IMBC) and species. To test this hypothesis we created a model bile composed exclusively of micelles, a solution containing micelles and vesicles, and a model bile containing all vesicles, as demonstrated by quasielastic light scattering. Gel filtration on Sepharose 4B demonstrated that model vesicles and micelles could be separated on a column eluted with buffer containing bile salt at the IMBC. However, a modest decrease in the buffer bile salt concentration (less than 1 mmol/L) resulted in complete conversion of micelles to vesicles. A comparable increase in the buffer bile salt concentration converted vesicles to micelles. Using only taurocholate in the eluting buffer at the IMBC caused a complete shift of micelles to vesicles, whereas using only taurochenodeoxycholate resulted in conversion of vesicles to micelles. An initial collection of rat bile separated on a column equilibrated with the measured IMBC demonstrated that 94% of the cholesterol was in the micellar fractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Serum lipid and fecal bile acid changes with cereal, vegetable, and sugar-beet fiber feeding.

Thirty-four subjects consumed six controlled formula diets for 3 wk each, supplemented with 0 g added fiber, 10 and 30 g dietary fiber as wheat bran (WB), 10 and 30 g dietary fiber as mixed vegetable fiber (VF), and 30 g dietary fiber as sugar-beet fiber (SBF). Serum cholesterol changes for fiber free, 10 g WB, 30 g WB, 10 g VF, 30 g VF, and 30 g SBF (-0.13, -0.18, -0.05, -0.17, -0.24, and -0.70 mmol/L, respectively) were significant for 30 g VF and 30 g SBF. Reduction in total cholesterol with SBF was largely due to significant lowering of low-density-lipoprotein cholesterol. Total fecal bile acid concentrations were significantly higher with the fiber-free diet than with 30 g WB, VF, and SBF (P less than 0.001) and were also higher with 30 g SBF than with 30 g WB and 30 g VF (P less than 0.005). Daily fecal bile acid excretion was not different on 30 g SBF compared with 30 g WB and 30 g VF. Differences in cholesterol reduction across the diets could not be explained by differences in fecal bile acid excretion.

Adult↗
PubMed1991

Liver denervation does not alter the circadian rhythm of bile acid synthesis in rats.

In both rats and humans there is a distinct circadian rhythm of bile acid synthesis that is independent of feedback regulation. To determine whether the circadian rhythm is directly mediated via hepatic nerves, bile acid synthesis was studied in selectively liver-denervated male Sprague-Dawley rats in a bile fistula model. Complete denervation was confirmed by histofluorescent staining for neural elements in frozen sections of livers. There was no significant difference in mean bile acid synthesis, amplitude of the circadian rhythm, or time of peak synthesis between the denervated rats and nondenervated controls. In one denervated rat studied four times at weekly intervals, there was no shift in acrophase, indicating that the rhythm had not become free running. We conclude that signals arriving via hepatic nerves neither directly cause nor entrain the circadian rhythm of bile acid synthesis in rats.

Animals↗
PubMed1991

Role of cholesterol synthesis in regulation of bile acid synthesis and biliary cholesterol secretion in humans.

We used lovastatin, a specific inhibitor of HMG-CoA reductase, to study the role of cholesterol synthesis in regulation of both bile acid synthesis, measured by release of 14CO2 from [26-14C]cholesterol, and biliary cholesterol secretion, measured by standard marked perfusion techniques, in humans. Six volunteers were studied in each of four periods: a) control; b) 6-10 hours after a single 40 mg oral dose of lovastatin to study acute effects; c) after 5-6 weeks of lovastatin 40 mg orally twice a day to study steady-state effects; and d) 24 h after cessation of chronic lovastatin. Mean bile acid synthesis fell to 69% of control (P less than 0.01) after single-dose lovastatin and remained at 83% of control after 5-6 weeks on lovastatin (P less than 0.05). After withdrawal of lovastatin, mean bile acid synthesis was 88% of control (NS). Mean biliary cholesterol secretion did not change after single-dose lovastatin (103% of control), but fell to 81% of control during chronic lovastatin treatment (P less than 0.05). After withdrawal of lovastatin, mean cholesterol secretion remained at 80% of control (P less than 0.05). These data suggest that in humans cholesterol synthesis is an immediate regulator of bile acid synthesis. Cholesterol synthesis also regulates biliary cholesterol secretion, but the effect is not immediate and therefore may be indirect.

Aged↗
PubMed1991

Effects of lovastatin on biliary lipid secretion and bile acid metabolism in humans.

Lovastatin, an inhibitor of HMG-CoA reductase, lowers cholesterol saturation of bile. To determine the mechanism of this effect and further define the role of cholesterol synthesis in regulation of biliary lipid metabolism, we studied ten human volunteers in a control period and again after 5-6 weeks on lovastatin, 40 mg b.i.d. Mean sterol production from acetate in mononuclear leukocytes fell from 1.18 to 0.84 pmol/min per 10(6) cells on lovastatin (P less than 0.02). Concomitantly there was reduction in mean biliary secretion of cholesterol from 143 to 96 mumol/h (P less than 0.02). On lovastatin, mean pool size of bile acids by the Lindstedt method fell from 3193 to 2917 mumol (one-sided P = 0.05) and mean pool size by the one-sample method fell from 5158 to 4091 mumol (P less than 0.002). Lovastatin had no effect on mean fractional turnover rate of either cholic acid (0.77 vs. 0.74 day-1) or chenodeoxycholic acid (0.51 vs. 0.54 day-1). Mean total bile acid synthesis was lower on lovastatin (1443 vs. 1240 mumol/day), but the difference did not quite achieve statistical significance. In humans, inhibition of cholesterol synthesis by lovastatin lowers biliary cholesterol saturation by reducing cholesterol secretion into bile. Bile acid pool size, and perhaps bile acid synthesis, are also reduced by this inhibition.

Adult↗
PubMed1990

Pathogenesis of gallstones: implications for management.

How do gallstones form, and what can be done to reverse or prevent the process? Bile acid physiology and pathophysiology are reviewed, especially with respect to cholesterol stones, and bile acid treatment to dissolve them is discussed. Although less well understood, the pathogenesis of pigment (black or brown) stones may involve bilirubin or carbonate salts, or infection.

Aging↗
PubMed1979

Diurnal rhythms of bile acid production in the rat.

Diurnal rhythms of bile acid synthesis were studied in Sprague-Dawley rats maintained in 12 h of illumination and 12 h of darkness each day. Synthesis, measured as output from a chronic bile fistula, underwent a consistent diurnal change with an amplitude of about 20% around mean daily synthesis and a peak in the dark period. The peak in cholate synthesis preceded the peak in chenodeoxycholate synthesis which preceded the peak in alpha-muricholate synthesis which preceded the peak in beta-muricholate synthesis. Fasting, intravenous infusion of dexamethasone (100 microgram/kg . h), adrenalectomy, and ocular enucleation all failed to abolish the diurnal rhythm in synthesis. In one rat studied 30 days after ocular enucleation the diurnal rhythm in synthesis persisted; however, relative to 4 days after enucleation the phase of the rhythm shifted about 90 degrees suggesting that light deprivation caused the rhythm to become free-running with a period slightly different from 24 h.

Adrenal Glands↗
PubMed1978

Sex differences in the size of bile acid pools.

In view of the excess prevalence of gallstones among women and the association of gallstones with diminished bile acid pool size, we measured bile acid pools in 27 male and 25 female healthy human volunteers. The average bile acid pool in the women was significantly smaller than in the men (2.25 +/- .12 g versus 2.88 +/- .16 g; p = 0.003). Chenodeoxycholic acid pool size, computed from bile acid composition data available in 43 of these subjects, was also smaller in women than men (0.94 +/- 0.06 versus 1.22 +/- 0.07 g; p = 0.004). Age, race, and body size bore no statistically significant relationship to bile acid pool size. Biliary cholesterol saturation was positively correlated with weight and obesity and showed a significant inverse correlation with chenodeoxycholic acid pool size, but not with total bile acid pool size. These findings suggest a possible mechanism for the higher prevalence of gallstones among women.

Adolescent↗
PubMed1978

Bilary lipids and bile acid pool size after vagotomy in man. Evidence against a predisposition to gallstones.

Eight male subjects who had previously undergone vagotomy and pyloroplasty were found to have significantly larger bile acid pools than did a group of matched control subjects. Associated with these expanded pools was a significantly lower molar per cent cholesterol of gallbladder bile in the vagotomy group. These findings are the opposite of those expected in a group predisposed to cholesterol cholelithiasis, suggesting that vagotomy, at least in males, does not predispose to cholesterol gallstones. If such stones form after vagotomy, they presumably do so by a mechanism not presently appreciated.

Bile↗
PubMed1977

Hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity in hamsters on a lithogenic diet.

The activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme for liver cholesterol biosynthesis, has been determined in young hamsters given a diet known to produce cholesterol gallstones in this species and compared to the activity found in chow-fed hamsters. None of the hamsters fed the lithogenic diet for 15 days or less developed gallstones but 74 percent of those on the diet for 26 to 49 days had cholesterol gallstones. None of the chow-fed animals developed gallstones. The mean HMG CoA reductase activity of hamsters on the lithogenic diet at 4 to 6 hours after the onset of the dark period was 20 times greater than in hamsters in the fasting state and 12 times that of fed hamsters on the chow diet. These greatly elevated enzyme activities were found as early as 2 to 15 days on the lighogenic diet and thus long before the gallstones appeared. The percentage of the bile acid pool represented by chenodeoxycholic acid was significantly higher, and that cholic acid correspondingly lower on the gallstone-inducing diet. This shift in bile acid composition may have contributed to gallstone formation. No significant accumulation of cholesterol was noted in liver or carcass. Increased synthesis of cholesterol induced by the greatly stimulated enzyme activity in hamsters on the lithogenic diet could account for the increased secretion of cholesterol in bile noted by others with subsequent supersaturation of gallbladder bile with respect to cholesterol, and then gallstone formation.

Alcohol Oxidoreductases↗