PubMed Health⌕ Search

Biomedical subjects

K D Setchell

Publications and source records attributed to K D Setchell.

At least 55 records · Page 3Linked to original sources
PubMed1994

Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women.

The influence of a diet containing soy protein on the hormonal status and regulation of the menstrual cycle was examined in six premenopausal women with regular ovulatory cycles. Soy protein (60 g containing 45 mg isoflavones) given daily for 1 mo significantly (P < 0.01) increased follicular phase length and/or delayed menstruation. Midcycle surges of luteinizing hormone and follicle-stimulating hormone were significantly suppressed during dietary intervention with soy protein. Plasma estradiol concentrations increased in the follicular phase and cholesterol concentrations decreased 9.6%. Similar responses occur with tamoxifen, an antiestrogen undergoing clinical trial as a prophylactic agent in women at high risk for breast cancer. These effects are presumed to be due to nonsteroidal estrogens of the isoflavone class, which behave as partial estrogen agonists/antagonists. The responses to soy protein are potentially beneficial with respect to risk factors for breast cancer and may in part explain the low incidence of breast cancer and its correlation with a high soy intake in Japanese and Chinese women.

Adult↗
PubMed1994

Effect of fasting on the enterohepatic circulation of bile acids in rats.

Fasting Sprague-Dawley rats for 72 h resulted in inhibition of bile salt synthesis, reduced bile flow and bile salt secretion rate, and reduced duodenal and portal venous bile acid concentrations. The initial rate of ileal brush border membrane (BBM) taurocholate (TC) uptake was markedly reduced in the fasted group (45% of control). TC uptake by BBM was saturable, with similar maximal transport velocity for the fasted rats and controls (1.69 +/- 0.06 and 1.62 +/- 0.017 nmol.mg protein-1.min-1, respectively) but higher Michaelis-Menten constant for fasted rats than for controls (96.9 +/- 20.0 and 54.9 +/- 10.2 microM, respectively). Hepatic basolateral membrane (BLM) TC uptake was enhanced by 65% in fasted animals. Transport kinetics in BLM had a similar Michaelis-Menten constant for fasted rats and controls (31.6 +/- 8.2 and 27.3 +/- 4.7 microM, respectively), and maximal transport velocity was higher for fasted rats than for controls (1.84 +/- 0.017 and 1.11 +/- 0.014 nmol.mg protein-1.min-1). The cholesterol-to-phospholipid ratio and fluorescence anisotropy in BLM of fasted rats decreased, and the cholesterol-to-phospholipid ratio and fluorescence anisotropy increased in ileal BBM. Alterations in the enterohepatic circulation of bile acids with fasting may alter expression of transport proteins for bile salts by direct effects on synthesis or indirectly through membrane lipid compositional changes.

Animals↗
PubMed1994

Effects of infant nutrition on cholesterol synthesis rates.

Nutrient effects on cholesterol fractional synthesis rates (FSR) in infancy by stable isotope determination have not been studied. We hypothesized that FSR is significantly reduced with high dietary cholesterol and phytoestrogen intake and increased with low dietary cholesterol and phytoestrogen intake. We prospectively studied 33 term male infants exclusively fed human milk (high cholesterol, low phytoestrogen, n = 12), cow milk-based formula (low cholesterol, low phytoestrogen, n = 8), soy milk-based formula (zero cholesterol, high phytoestrogen, n = 7), or soy milk-based formula modified to contain cholesterol (low cholesterol, high phytoestrogen, n = 6) during the first 4 mo of life. Cholesterol FSR was determined from rate of incorporation of deuterium into erythrocyte membrane cholesterol, and urinary isoflavone excretion (an index of dietary phytoestrogen exposure) was measured by gas chromatography-mass spectrometry. Significant differences in cholesterol FSR were found. FSR (%/d) was lowest in human milk (2.62 +/- 0.38), highest in soy milk-based formula (9.40 +/- 0.51), and intermediate in cow milk-based and modified soy milk-based formula (6.90 +/- 0.48 and 8.03 +/- 0.28, respectively), p < 0.0001. Cholesterol FSR was significantly lower in modified soy milk-based compared with soy milk-based formula, p < 0.05. We also show for the first time that dietary phytoestrogens are absorbed and excreted by the infant fed soy protein-based formula. Urinary isoflavone excretion was inversely related to cholesterol FSR, but it was not significantly related to serum cholesterol concentration. We conclude that the type of infant nutrition and dietary cholesterol are major factors influencing cholesterol fractional synthesis rates in infancy.

Adaptation, Physiological↗
PubMed1994

Purification and characterization of a novel 17 alpha-hydroxysteroid dehydrogenase from an intestinal Eubacterium sp. VPI 12708.

A novel steroid-inducible 17 alpha-hydroxysteroid dehydrogenase (17 alpha-HSDH) has been purified over 850-fold from an intestinal Eubacterium sp. VPI 12708. The purified protein has a subunit molecular mass of 42,000 daltons and a native molecular weight (M(r)) of 160,000 as estimated by gel filtration chromatography. Enzyme activity was induced by growth in the presence of androstenedione or cholic acid, but not deoxycholic acid. Enzymatic activity required anaerobic conditions and was highly specific for NADP+ and the 17 alpha-hydroxy group of C-19 steroids. Estimated Km values were 31 microM and 70 microM for androstenedione and epitestosterone, respectively. Vmax values were estimated to be 3250 nmol/min per mg protein and 1800 nmol/min per mg protein for the reductive and oxidative reactions, respectively. The pH optima for both the oxidative and reductive reactions ranged between 5.5 and 7.0. Treatment with EDTA completely inactivated 17 alpha-HSDH activity but activity was partially restored by the addition of either Mg2+ (1 mM) or Zn2+ (10 mM). The N-terminal amino acid sequence analysis of purified enzyme suggests that 17 alpha-HSDH may belong to a disulfide reductase gene family.

Amino Acid Sequence↗
PubMed1994

Metabolism and effect of 7-oxo-lithocholic acid 3-sulfate on bile flow and biliary lipid secretion in rats.

Significant amounts of oxo and sulfated bile acids are excreted in the urine of patients with cholestatic liver diseases, but these bile acid species are found only in traces in bile. Several possible explanations for this finding include poor canalicular secretion, rapid biotransformation by oxidoreduction and extrahepatic sulfation of oxo bile acids. To assess the physiological actions and hepatic metabolism of oxo and sulfated bile acids, we synthesized 7-oxo-lithocholic acid 3-sulfate, examined the effect of intravenous infusion of this bile acid (5.0 mumol/min/kg body wt) on bile flow and biliary lipid secretion in Sprague-Dawley rats with a bile fistula and compared this effect with that of the unconjugated analog, 7-oxo-lithocholic acid, and the primary bile acid conjugate, chenodeoxycholic acid 3-sulfate. Bile flow and bile acid secretion increased immediately after infusion of all three bile acids. The highly polar 7-oxo-lithocholic acid 3-sulfate significantly reduced the biliary secretion of phospholipids (p < 0.05) and cholesterol (p < 0.05), but by contrast the more hydrophobic analog, 7-oxo-lithocholic acid, caused a significant increase in the biliary phospholipids (p < 0.001) and cholesterol (p < 0.01) secretion. Infusion of chenodeoxycholic acid 3-sulfate also resulted in an increase in secretion of biliary cholesterol and phospholipids, but the magnitude of the change was less than that induced by 7-oxo-lithocholic acid infusion. Biliary lipid secretion was inversely related to the polarity of the infused bile acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

5 beta-hydroxylation by the liver. Identification of 3,5,7-trihydroxy nor-bile acids as new major biotransformation products of 3,7-dihydroxy nor-bile acids in rodents.

24-Norursodeoxycholic acid (nor-UDCA), when administered into the anesthetized biliary fistula hamster or injected into the perfusate of an isolated liver, was hydroxylated at C-5 to give 5 beta-hydroxynorursodeoxycholic acid 2 (3 alpha,5,7 beta-trihydroxy-24-nor-5 beta-cholan-23-oic acid), which was secreted into bile mainly as such. Similarly, 24-norchenodeoxycholic acid (nor-CDCA) was 5 beta-hydroxylated to give 5 beta-hydroxynor-chenodeoxycholic acid 4 (3 alpha,5,7 alpha-trihydroxy-24-nor-5 beta-cholan-23-oic acid), which was also secreted into bile without appreciable further biotransformation. The site of hydroxylation was assigned by 13C and 1H NMR and mass spectrometry. 5-Hydroxylation was a major biotransformation pathway at physiological bile acid loads. 5-Hydroxylation of UDCA also occurred in the perfused rat liver but to a lesser extent. 5-Hydroxylation of nor-UDCA was not observed in rabbit, dog, or man, indicating that its formation is species-specific. 5-Hydroxylation of nor-CDCA and nor-UDCA is the first reported example of hydroxylation of a tertiary carbon atom of bile acids. Nor-dihydroxy bile acids appear to be useful for the detection of minor hydroxylation pathways, because their prolonged hepatobiliary retention exposes them repeatedly to hydroxylases present in the hepatobiliary system.

Animals↗
PubMed1993

Analysis of faecal neutral sterols in patients with familial adenomatous polyposis by gas chromatography-mass spectrometry.

Previous studies have suggested that patients with familial adenomatous polyposis (FAP) have increased faecal excretion of cholesterol but a reduction in cholesterol metabolites. It was consequently proposed that the degree of faecal cholesterol degradation could be used as a means of diagnosis. Developments in the extraction and analysis of faecal neutral sterols as well as the accurate means of diagnosing FAP by DNA analysis and indirect ophthalmoscopy has necessitated a re-examination of this proposal. Faecal neutral sterols were analysed in 10 patients with untreated FAP following a complete 5-day stool collection and compared with 9 healthy control subjects (including 4 siblings) closely matched for age and sex. The median [25 and 75, percentiles] stool wet weights were similar between the FAP (97.5 [69, 192] g.24 h-1) and the control (116 [61.5, 137] g.24 h-1) groups. Faecal cholesterol concentration was similar in the two groups (FAP = 2.3 [1.4, 4.2]; control = 3.5 [1.0, 6.0] mumol.g-1 dry wt) as was the concentration of total neutral sterols not including plant sterols (FAP = 17.2 [13.4, 21.0]; control = 18.2 [7.4, 21.6] mumol.g-1 dry wt). There were no significant differences in the proportions of cholesterol metabolised between the FAP (82.3 [74.2, 93.5]%) and control (72.1 [5.7, 81.3]%) groups. This study does not support the notion that faecal neutral sterol metabolism is uniquely different in patients with FAP.

Adenomatous Polyposis Coli↗
PubMed1993

Formation, absorption, and biotransformation of delta 6-lithocholenic acid in humans.

delta 6-Lithocholenic acid was identified in small amounts in fecal samples in vitro after incubation with ursodeoxycholic acid and in vivo in controls and after chenodeoxycholic and ursodeoxycholic acid ingestion. Fourteen to 45.0% of delta 6-[24-14C]lithocholenic acid was biotransformed in vitro in feces within 30 s. After colonic instillation of delta 6-[24-14C]lithocholenic acid, 50% of the radioactivity appeared in bile acids, most of it in lithocholic acid, within 3 h. Jejunal perfusions with delta 6-[24-14C]lithocholenic acid showed 33-92% absorption. One hour after jejunal instillation of 1 mmol, 4.4-27.5% of the biliary radioactivity was found in ursodeoxycholic, chenodeoxycholic, lithocholic, and 7-ketolithocholic acids. A sulfated glycine conjugate of delta 6-lithocholenic acid was identified in bile. One hour after intravenous injection of delta 6-[24-14C]lithocholenic acid, 40.1-42.6% of biliary radioactivity appeared in 7-ketolithocholic, chenodeoxycholic, lithocholic/isolithocholic, and ursodeoxycholic acids. The studies show that delta 6-lithocholenic acid is 1) formed in colonic lumen from chenodeoxycholic and ursodeoxycholic acids, 2) well absorbed in small intestine, and 3) biotransformed in both the colonic lumen and liver. The studies also identified delta 6-lithocholenic acid as a new intermediate in formation of lithocholic acid. Finally, the studies showed that a small portion of delta 6-lithocholenic acid is excreted as a sulfated glycine conjugate in bile.

Bile↗
PubMed1993

An anion exchanger mediates bile acid transport across the placental microvillous membrane.

Microvillous membrane vesicles from the term human placental syncytiotrophoblast were used to characterize further the properties of a transport mechanism for bile acids. Taurocholate (TC) uptake into an osmotically reactive intravesicular space was temperature dependent and independent of sodium. TC uptake (2 microM) was markedly inhibited by 250 microM taurine and glycine-conjugated cholate and chenodeoxycholate and unconjugated cholate but not by chenodeoxycholate, deoxycholate, etianic acid, bromosulfophthalein, pyruvate, lactate, alanine, or taurine. The initial rate of TC uptake was inhibited significantly by the anion transport inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) but was not inhibited significantly by 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid, amiloride, or furosemide. Preincubation of vesicles with DIDS in the presence of TC partially blocked the action of the inhibitor. Efflux of 5 microM TC from membrane vesicles was stimulated by the presence of 50 microM TC in the incubation media. Basal as well as transstimulated TC efflux was inhibited by DIDS. The initial rate of TC influx followed saturation kinetics with an apparent Michaelis constant of 112 +/- 23 microM and maximal velocity of 2.01 +/- 0.19 nmol.mg protein-1.min-1. When the transmembrane electrical potential difference across the brush-border membrane vesicles was altered by external anion replacement or by valinomycin-induced K+ diffusion potentials, TC uptake was not significantly affected. DIDS-sensitive TC uptake was stimulated two-to threefold by an outwardly directed hydroxyl gradient (pH 7.7in/5.5out) compared with TC influx under pH-equilibrated conditions (pH 7.7in/7.7out). These studies are consistent with an electroneutral anion-exchange mechanism that mediates transfer of conjugated bile acids across the microvillous membrane of the syncytiotrophoblast.

Anion Exchange Resins↗
PubMed1993

Resolution of liver biopsy alterations in three siblings with bile acid treatment of an inborn error of bile acid metabolism (delta 4-3-oxosteroid 5 beta-reductase deficiency).

Identical male twins and their brother, cholestatic from birth, with delta 4-3-oxosteroid 5 beta-reductase deficiency, were studied by serial liver biopsy. Spectrometry documented defective primary bile acid synthesis and markedly increased levels of atypical oxo and allo bile acids in urine and serum. Hepatocellular cholestasis and giant-cell transformation resolved in parallel with clinical and biochemical recovery during oral bile acid administration. In the twins, portal fibrosis stabilized at a mild level; they are well as 5-yr-olds at this writing. Follow-up biopsy in their brother at 8 mo was normal, and he is doing well at 3 yr of age. Hepatic ultrastructural alterations in all three were characterized by abnormalities of bile canaliculi including small bile plugs, diverticulae and latticelike elaborations of hepatocellular membranes adjacent to bile canaliculi that were shown to have resolved completely on subsequent biopsies. Eight additional cases have been detected on urine screening; only two of these patients have survived, on bile acid therapy. Early diagnosis and treatment improves the prognosis of this otherwise lethal inborn error of bile acid synthesis.

Bile Acids and Salts↗
PubMed1992

Bile acid biosynthesis.

To conclude, the last several years have seen a resurgence of interest in the biosynthesis of bile acids. This focus has come about due to the central roles that these molecules play in cholesterol and fat metabolism and due to recent advances in their chemistry, biochemistry, and molecular biology. The application of probes generated by these methodologies has begun to generate novel insight into bile acid metabolism, regulation, and genetics. The next several years should be equally exciting.

Animals↗
PubMed1992

Oral bile acid treatment and the patient with Zellweger syndrome.

The cerebrohepatorenal syndrome of Zellweger is a congenital syndrome of multiple manifestations, including hepatomegaly and liver dysfunction. Treatment is generally of a supportive nature, aimed at improving nutrition and growth, controlling the central nervous system symptoms and limiting progression of liver disease. Because the liver disease in Zellweger syndrome may be attributed to an overproduction and accumulation of cholestanoic acids, exacerbated by diminished primary bile acid synthesis, we hypothesized that primary bile acid administration would be beneficial in improving liver function by a mechanism involving down-regulation in the synthesis of these atypical bile acids. We report here the clinical and biochemical responses to primary bile acid administration in a 2-mo-old boy who was seen with the typical signs of Zellweger syndrome. Liver disease was evident from hepatomegaly and elevated serum liver enzymes and bilirubin. The diagnosis was supported by markedly elevated serum very long chain fatty acids and the bile acids dihydroxycholestanoic acid and trihydroxycholestanoic acid. Confirmation of the lack of peroxisomes was established by electron microscopy. When the patient was 6 mo old, the primary bile acids cholic acid and chenodeoxycholic acid, (100 mg each/day) were administered orally. A significant improvement in biochemical indices of liver function occurred with a normalization of the serum bilirubin and liver enzymes and a histological improvement in the extent of inflammation and bile duct proliferation and disappearance of cannalicular plugs. Serum and urinary cholestanoic acids showed a significant decrease within a few days. A striking and sustained increase in growth was observed after therapy, and an improvement in neurological symptoms was noted. In conclusion, this study indicates that primary bile acid therapy improves liver function and growth in the patient with peroxisomal dysfunction and should be considered in the supportive therapies for this condition.

Administration, Oral↗
PubMed1992

Ursodeoxycholic acid therapy in cystic fibrosis-associated liver disease: a dose-response study.

Previous studies from our groups have demonstrated improvements in biochemical markers of liver function when cystic fibrosis patients with associated liver disease were administered oral ursodeoxycholic acid. The magnitude of the response was somewhat less than that found when comparable doses (10 to 15 mg/kg body wt/day) of ursodeoxycholic acid are given to other liver disease patients; this may be explained by the bile acid malabsorption that is characteristic of the disease. For this reason a dose-response study was carried out in nine cystic fibrosis patients with liver disease to establish whether improved efficacy could be obtained with higher doses. Ursodeoxycholic acid in doses of 5, 10 and 15 mg/kg body wt/day was given orally for consecutive 2-mo periods in a replicated Latin-square design. After this, all patients received 20 mg/kg body wt/day. Liver function, individual serum bile acids and biliary bile acid composition were determined at entry and at the end of each treatment period. Our data demonstrate that the magnitude of the biochemical improvement in serum liver enzymes was significantly greater with higher doses of ursodeoxycholic acid; at 20 mg/kg body wt/day it was similar to that reported for patients with other liver diseases administered lower doses. Biliary ursodeoxycholic acid enrichment increased with increasing doses, attaining 42% +/- 6% of the total biliary bile acids with the highest dose. Fasting serum ursodeoxycholic acid concentrations increased during ursodeoxycholic acid administration but were variable and correlated poorly with the dose of ursodeoxycholic acid administered, whereas no correlation was found between serum ursodeoxycholic acid concentration and the proportion of ursodeoxycholic acid in bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Bile Acids and Salts↗
PubMed1992

Ileal resection/dysfunction in childhood predisposes to lithogenic bile only after puberty.

Children with ileal resection/dysfunction since infancy have bile that is not supersaturated with cholesterol. Five sexually mature subjects (age 16-19 years) who had been previously investigated in childhood (age 4-9 years) were studied. Gallstones were found in one. Bile rich duodenal aspirates were analyzed for lipid content (molar fraction) and the cholesterol saturation index was calculated. In the postpubertal subjects, a significantly higher proportion of biliary cholesterol (22.0% +/- 4.8% vs. 3.2% +/- 0.6% and 5.7% +/- 0.5%, P less than 0.005) and significantly lower bile acids (58.1% +/- 3.9% vs. 79.7% +/- 2.3% and 78.2% +/- 1.9%, P less than 0.005) were found compared with the initial (prepubertal) samples or in samples from 20 healthy young adults. The cholesterol saturation index was significantly higher (3.1 +/- 0.7 vs. 0.6 +/- 0.1 and 1.1 +/- 0.1, P less than 0.005) whereas phospholipid content did not change (19.9% +/- 1.6% vs. 17.1% +/- 1.8% and 16.6% +/- 1.6%) as compared with themselves before puberty and as healthy young adults, respectively. It was concluded that children with ileal resection/dysfunction do not appear at risk for cholesterol cholelithiasis before puberty; however, the development of biliary cholesterol supersaturation after puberty may predispose them to gallstone formation in adulthood.

Adolescent↗
PubMed1992

A proposed nomenclature for bile acids.

A proposal is made for a system of nomenclature of the more common unconjugated and conjugated bile acids. Acceptable trivial names for bile acids are tabulated, and guidelines are proposed for using these existing trivial names as roots to create acceptable semi-systematic names for other bile acids, as well as for new natural bile acids that will be discovered in the future. The term alpha-hyocholic is recommended to replace hyocholic, and beta-hyocholic to replace omega-muricholic. The term murideoxycholic acid is recommended for 3 alpha,6 beta-dihydroxy-5 beta-cholan-24-oic acid. Proposals are also made for bile acids with epimeric hydroxy groups, for unsaturated bile acids, and for bile acids with oxo- and/or hydroxy-oxo- substituents on the nucleus and/or on the side chain. For conjugated bile acids, the term "aminoacyl amidates" is recommended to replace "amidates" for bile acids conjugated in N-acyl linkage with amino acids. Nomenclature for other types of conjugates (sulfates, glucuronides, glucosides) is included as well as abbreviations. It is recommended that the historic tradition of naming a newly discovered bile acid after the species from which it was isolated be abandoned, and that in the future such a bile acid should be named using the principles contained in this paper.

Bile Acids and Salts↗
PubMed1991

Analysis of vitamin D and its metabolites using thermospray liquid chromatography/mass spectrometry.

A new method is described for the analysis of vitamin D and its metabolites utilizing thermospray (TSP) mass spectrometry as an on-line detector for high performance liquid chromatography. Ionization conditions were optimized for use with isocratic reversed phase chromatography. TSP mass spectrometry was employed in series with a UV absorbance detector to facilitate comparisons between the two methods of detection. Positive ion TSP mass spectra were recorded for vitamin D2, vitamin D3, 25-hydroxyvitamin D3 (25(OH)D3), 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3). The spectra contained protonated molecular ions, ammonium adduct ions and fragment ions due to the loss of one or more molecules of water. A comparison of quantitative precision was made by determining UV absorbance and TSP standard curves for vitamin D3 using two different methods: (1) External standard method with post-column (post UV detector) addition of ammonium acetate. (2) As (1) but using the method of internal standards with a closely eluting internal standard (vitamin D2). In each case the quantitative precision (correlation coefficient) for UV absorbance detection was superior owing to intrinsic instability of the TSP ion beam. A stable isotopically labelled internal standard was employed in the development of an assay for 1,25(OH)2D3. The assay was used to quantify in vitro enzymic conversion of 25(OH)D3 to 1,25(OH)2D3 in guinea pig and sheep renal mitochondrial incubations. TSP LC/MS was also applied to analysis of an extract of human blood plasma in which D3 and each of its principal metabolites were identified in a single analysis.

24,25-Dihydroxyvitamin D 3↗
PubMed1991

Lack of teratogenicity of trans-2-ene-valproic acid compared to valproic acid in rats.

The teratogenicity of trans-2-ene-valproic acid (300 and 400 mg/kg) was compared with that of valproic acid (VPA; 300 mg/kg) and controls (corn oil) administered by gavage to Sprague-Dawley CD rats on embryonic (E) days 7-18. At the 300 mg/kg dose, trans-2-ene-VPA produced no change in maternal weight, number of implantations, proportion of resorptions, proportion of malformations, or fetal weight. By contrast, the same dose of VPA (300 mg/kg) reduced maternal weight during gestation, increased malformations (12.0% vs. 0.7% in controls), and reduced fetal body weight by 25.1%. An even higher dose of trans-2-ene-VPA (400 mg/kg) produced a reduction in maternal body weight during treatment and reduced fetal body weight (by 7.9%), but did not increase resorptions or malformations in the fetuses. On day E18, maternal serum drug concentrations of VPA were higher in the VPA-treated group compared with those of trans-2-ene-VPA in the trans-2-ene-VPA-treated groups at 1 hr posttreatment. At 6 hr posttreatment the reverse was seen. trans-2-ene-VPA may be absorbed more rapidly and distributed differently than VPA. Overall, the data support the view that trans-2-ene-VPA at equal or higher doses than VPA is not teratogenic in rats.

Animals↗