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Biomedical subjects

K D Setchell

Publications and source records attributed to K D Setchell.

At least 109 records · Page 6Linked to original sources
PubMed1987

Familial giant cell hepatitis associated with synthesis of 3 beta, 7 alpha-dihydroxy-and 3 beta,7 alpha, 12 alpha-trihydroxy-5-cholenoic acids.

Urinary bile acids from a 3-mo-old boy with cholestatic jaundice were analyzed by ion exchange chromatography and gas chromatography-mass spectrometry (GC-MS). This suggested the presence of labile sulfated cholenoic acids with an allylic hydroxyl group, a conclusion supported by analysis using fast atom bombardment mass spectrometry (FAB-MS). The compounds detected by FAB-MS were separated by thin layer chromatography and high performance liquid chromatography. The sulfated bile acids could be solvolyzed in acidified tetrahydrofuran, and glycine conjugates were partially hydrolyzed by cholylglycine hydrolase. Following solvolysis, deconjugation, and methylation with diazomethane, the bile acids were identified by GC-MS of trimethylsilyl derivatives. The major bile acids in the urine were 3 beta,7 alpha-dihydroxy-5-cholenoic acid 3-sulfate, 3 beta,7 alpha,12 alpha-trihydroxy-5-cholenoic acid monosulfate, and their glycine conjugates. Chenodeoxycholic acid and cholic acid were undetectable in urine and plasma. The family pedigree suggested that abnormal bile acid synthesis was an autosomal recessive condition leading to cirrhosis in early childhood.

3-Hydroxysteroid Dehydrogenases↗
PubMed1987

Biliary bile acid composition of the human fetus in early gestation.

Using analytical techniques, which included capillary column gas-liquid chromatography and mass spectrometry, detailed bile acid profiles were obtained for 24 fetal bile samples collected after legal abortions were performed between the 14th and 20th wk of gestation. Qualitatively, the bile acid profiles of all fetal bile samples were similar. The predominant bile acids identified were chenodeoxycholic and cholic acid. The presence of small but variable amounts of deoxycholic acid and traces of lithocholic acid suggested placental transfer of these bile acids from the maternal circulation. 3 beta-Hydroxy-5-cholenoic acid was detected at higher levels than lithocholic acid. A conspicuous feature of the profiles was the presence of bile acids with hydroxyl groups at positions C-1 and C-6, and one other nuclear position of unknown origin, indicating fetal hepatic synthesis via pathways different from those normally seen in the adult. Quantitatively total biliary bile acid concentrations were extremely low (less than 0.05 mM) before wk 17 of gestation, but thereafter concentrations markedly increased reflecting a possible surge in bile acid synthesis; however, the ratio of cholic:chenodeoxycholic acids remained relatively constant over this period (mean +/- SD = 0.85 +/- 0.36) and different from that reported for the healthy newborn (ca. 2.5) and adult (ca. 1.6). These data indicate an immaturity in hepatic 12 alpha-hydroxylation of bile acids during early development and may explain why other pathways, in particular 1 beta and 6 alpha-hydroxylation, are activated at this stage of life.

Bile Acids and Salts↗
PubMed1987

Absence of an acinar gradient for bile acid uptake in developing rat liver.

We studied the acinar distribution for uptake of the bile acid analogue [125I]-cholylglycyltyrosine in livers from adult and 14-day-old suckling rats. Portal and peripheral (systemic) serum bile acid concentrations were also measured by combined gas chromatography-mass spectrometry as an independent index of hepatic bile acid clearance from portal blood. Utilizing light microscopic autoradiography, a steep, decreasing portal to centrilobular gradient for cholylglycyltyrosine uptake was noted in adult rat liver. In contrast, there was no lobular gradient for cholylglycyltyrosine uptake visible in the 14-day-rat liver; all hepatocytes within the acinus contained a similar number of silver grains. Portal vein total bile acid concentrations were significantly higher in serum of adult compared to 14-day-old rats. In contrast, bile acid concentrations were 10-fold higher in the peripheral serum of developing versus adult rats. The peripheral to portal serum bile acid concentration ratio was 0.23 in the adult and 6.48 in the 14-day-old rat. We conclude that the entire hepatic lobule participates in the uptake of bile acids in the 14-day-old rat even under the basal conditions of this study. The normal "reserve" function of centrilobular hepatocytes is not sufficient to compensate for the decreased transport capacity of the developing liver with the result that increased concentrations of bile acids enter and accumulate in the systemic circulation.

Aging↗
PubMed1986

Enzymatic synthesis and chromatographic purification of lignan glucuronides.

Enterolactone, enterodiol and secoisolariciresinol were conjugated with glucuronic acid by solubilized rabbit liver microsomal UDP-glucuronyltrasnferase. The monoglucuronide conjugate of all three substrates was formed and its identity confirmed by nuclear magnetic resonance (NMR) spectroscopy. Analytical high pressure liquid chromatography (HPLC) and NMR spectroscopy indicated conjugation with glucuronic acid to occur at several positions in the molecule. The enzymatic conjugation was monitored by analytical capillary isotachophoresis (ITP). The Km-values for enterlactone, enterodiol, and secoisolariciresinol were calculated to be 0.30, 0.23, and 0.22 mmol/l respectively.

Animals↗
PubMed1986

Detailed faecal bile acid profile: a diagnostic test for colorectal cancer?

Detailed profiles of bile acids in faeces were evaluated as a diagnostic test for colorectal cancer in rats. Twenty-seven bile acid peaks were measured using improved methods of extraction and separation followed by the sensitive and specific techniques of capillary column gas liquid chromatography and mass spectrometry. Colorectal cancer was induced in experimental animals (female Sprague-Dawley rats, n = 20) by subcutaneous injection of dimethylhydrazine (DMH) and faecal unconjugated bile acids compared with those in the control group (n = 20). The amount of total faecal unconjugated bile acids was lower in the animals administered DMH (255 mg/day vs 334 mg/day: (P = 0.04), and the excretion of seven individual bile acids was reduced when compared with those in the control group (P less than 0.01). In order to use the faecal bile acid profiles as a diagnostic test, linear discriminant analysis was performed. A discriminant score was derived which was applied to each profile, to determine to which group (control or DMH) each animal belonged retrospectively. All analyses were performed blind, and 90% of the animals were correctly assigned. In man, as in rats, the bile acid profile of faces is equally complex and the bile acid profile may be useful as a diagnostic test.

Animals↗
PubMed1985

Serum unconjugated bile acids: qualitative and quantitative profiles in ileal resection and bacterial overgrowth.

Qualitative and quantitative profiles of unconjugated bile acids in the serum obtained over a 24-h period from three patients with ileal resections and one with a bacterial overgrowth are described. Unconjugated serum bile acids were determined using the high sensitivity and resolution of capillary column gas liquid chromatography after their rapid extraction and isolation using reverse phase octadecylsilane bonded silica cartridges and the lipophilic gel Lipidex 1000. Unconjugated serum bile acid concentrations were elevated throughout the day in both ileum resected patients and in conditions involving bacterial overgrowth when compared to healthy subjects. Total conjugated cholic acid concentrations were expectedly low in both intestinal disorders and were without the postprandial increases generally observed in healthy subjects. Qualitative gas chromatographic profiles of serum unconjugated bile acids in bacterial overgrowth distinctly revealed a predominance of deoxycholic acid and other secondary bile acids in all samples, while, in conditions of an impaired enterohepatic circulation, deoxycholic acid was absent or present in only trace amounts. The potential significance of measuring serum unconjugated bile acids in intestinal disorders is discussed.

Adult↗
PubMed1985

Serum bile acid composition in patients with cystic fibrosis.

Serum bile acid composition was examined in detail using capillary column gas chromatography and mass spectrometry in 10 children with cystic fibrosis (CF) and 4 healthy children. The mean total bile acid concentration in fasting serum of CF patients was 2.33 +/- 0.84 mumol/l, slightly lower than but not statistically significantly different from healthy controls (mean 2.86 +/- 0.98 mumol/l) and appeared to show no relationship to the degree of exocrine pancreatic insufficiency. Analysis of individual serum bile acids in these children showed that cholic acid represented less than 10% of the total bile acids. Chenodeoxycholic acid was the predominant serum bile acid; the mean concentration in CF patients was 0.98 +/- 0.51 mumol/l, lower than for the healthy controls (1.69 +/- 0.84 mumol/l). Concentrations of lithocholic acid, 3 beta-hydroxy-5-cholenoic, ursodeoxycholic and 3 beta, 7 alpha, 12 alpha-trihydroxy-5 beta-cholanoic acids in fasting serum samples of the CF patients were not significantly different from the healthy control sera but were higher than those normally found in adults. Measurements of fecal bile acid excretion indicated an increased loss of primary bile acids in patients with CF consistent with an impairment of the enterohepatic circulation of bile acids.

Adolescent↗
PubMed1985

Production and metabolism of lignans by the human faecal flora.

Lignans have, until recently, been found only in plants. Enterolactone and enterodiol are the major lignans present in the urine of humans and have a potential physiological protective role against cancer. It has been shown that these compounds can be formed in vitro by human faecal flora and that enterodiol is oxidized to enterolactone by bacteria that are present in stools at a concentration of up to 10(3)/g. It was also possible to produce both of these lignans in vitro from linseeds and from secoisolariciresinol, a precursor present in linseed, by bacteria present in stools, at a concentration of between 10(3) and 10(4)/g. Enterolactone was produced from matairesinol, a more abundant plant lignan than secoisolariciresinol, after incubation with a mixed faecal flora under both aerobic and anaerobic conditions. In each case conversion was dependent on the presence of viable bacteria. These findings indicate that a number of different pathways operate to produce enterolactone and enterodiol depending on the ingested dietary precursor.

4-Butyrolactone↗
PubMed1985

Fecal bile acid profiles of Japanese patients with adenomatous polyps of the large bowel: special reference to distribution, multiplicity, size and degree of dysplasia of the polyps.

Bile acids have been implicated in carcinogenesis of the large bowel, and since epidemiological, clinical and histopathological studies suggest a link between adenomatous polyps and cancer of the large bowel, fecal bile acid profiles were studied in 33 patients with adenomatous polyps of the large bowel and these data were analyzed with particular reference to the distribution, multiplicity, size and degree of dysplasia of the polyps. The more polyps and the greater the severity of dysplasia, the higher was the excretion of total bile acids (mean mumol/day: single vs multiple polyps, 344.8 vs 369.1; mild vs moderate vs severe dysplasia, 347.5 vs 370.0 vs 399.3). However, in patients with larger polyps, total fecal bile acid excretion tended to be lower (mean mumol/day: large vs small polyps, 267.7 vs 389.5). These differences were not statistically significant. When fecal bile acid profiles were analyzed with respect to the extent of bacterial metabolism determined from the degree of dehydroxylation and oxidoreduction, there was a large variation with no consistency in relation to the factors studied among the polyp patients. Deconjugation of bile acids in feces was almost complete without difference among the patients. These results seem to indicate that the significance of bile acid in the development of adenomatous polyps in Japanese subjects is likely to be small.

Adult↗
PubMed1984

Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease.

Equol, a nonsteroidal estrogen of dietary origin, was recently identified in human urine, and is excreted in amounts comparable to the classical steroidal estrogens. We confirm here that phytoestrogens which are abundant in dietary soya protein are converted by human gastrointestinal flora to this weak estrogen. After the ingestion of meals containing cooked soya protein the urinary excretion of equol in four of six subjects studied increased by up to 1000-fold and this compound was the major phenolic compound found in the urine. These data also indicate that some subjects are unable to either produce or excrete equol despite the challenge of a diet containing soya. In view of the increasing use of commercial soya products in the diet and the capacity of human bacterial flora to synthesize this weak estrogen from the abundance of phytoestrogens in soya, the potential relevance of these observations to the diseases implicating steroid hormones is discussed.

Adult↗
PubMed1984

Comparison of faecal bile acid profiles between patients with adenomatous polyps of the large bowel and healthy subjects in Japan.

Faecal bile acid excretion was examined in 13 patients with adenomatous polyps of the large bowel and compared with a series of matched healthy subjects. Bile acids were analysed in detail with respect to the composition of individual bile acids and their mode of conjugation. The total excretion of bile acids by the patient group and the healthy subjects ranged from 55.0-837.6 mumol/day (median 233.8, mean 346.9) and 93.8-712.3 mumol/day (median 489.2, mean 386.7) respectively. Expressed as mumol/g faecal weight these values were 0.6-4.8 (median 2.2, mean 2.4) and 0.4-5.8 (median 2.2, mean 2.8) and in terms of mumol/g faecal dry weight, 1.9-50.7 (median 10.1, mean 16.5) and 3.9-32.4 (median 16.3, mean 16.7) respectively for the two groups. The composition of the individual bile acids and their distribution within the various conjugate fractions was essentially the same for both groups. Cholenoic acid (5 beta-chol-3-enoic acid), an unusual bile acid, was detected in one patient and three healthy subjects. These results revealed no significant quantitative differences in bile acid excretion between the group of patients with adenomatous polyps and those of healthy subjects.

Adult↗
PubMed1984

Soya--a dietary source of the non-steroidal oestrogen equol in man and animals.

The dietary origin of the weak oestrogen equol (7-hydroxy-3-(4'-hydroxyphenyl)-chroman) present in human urine has been investigated using gas chromatography-mass spectrometry. Feeding experiments with different food constituents and monitoring the urinary excretion of equol revealed that soya food yields more than 0.1 mg urinary equol/g flour ingested. From this source the glucoside of daidzein (4',7-dihydroxyisoflavone) has been isolated and identified as a precursor of equol. Both equol and daidzein were characterized as monoglucuronide conjugates in human urine and the concentration of urinary equol exceeded the concentrations of the classical oestrogens by 100- to 1000-fold after ingestion of a single meal containing soya protein. The potential biological significance of this result is discussed.

Adult↗
PubMed1983

Fat and cancer.

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Animals↗
PubMed1983

Serum bile acid analysis.

Routine and research techniques are outlined for the analysis of bile acids in serum. The basis of these techniques is the use of liquid-solid extraction and liquid-gel chromatography coupled with the measurement of bile acids by gas chromatography using high resolution glass capillary columns and mass spectrometry which provides increased sensitivity compared with conventional methods of measurement. Problems associated with the isolation and purification of bile acids from serum are discussed and rapid and flexible methods for their metabolic profiling are described. The advantages and applicability of these procedures are illustrated with examples of profiles of bile acids in the serum from normal subjects, patients with liver disease and a patient with an ileal resection.

Adult↗
PubMed1983

Measurement of enterolactone and enterodiol, the first mammalian lignans, using stable isotope dilution and gas chromatography mass spectrometry.

Methods are described to extract and measure 2,3-bis(3-hydroxybenzyl)-gamma-butyrolactone (enterolactone) and 2,3-bis(3-hydroxybenzyl)butane-1,4-diol (enterodiol) from physiological fluids. They are based on the use of stable labelled analogues of each compound as internal standards with end point assay being by gas chromatography mass spectrometry. The methods were developed to quantify enterolactone and enterodiol in experiments designed to investigate the significance and source of these compounds in man and animals. Examples of studies on human ovarian blood and investigations of their excretion in urine following dietary manipulation are described.

4-Butyrolactone↗
PubMed1983

General methods for the analysis of metabolic profiles of bile acids and related compounds in feces.

A general method is described for the detailed qualitative and quantitative analysis of bile acids and related compounds from feces. The technique utilizes a novel combination of liquid-gel and liquid-solid extraction, lipophilic ion exchange chromatography, and capillary column gas-liquid chromatography coupled to mass spectrometry, which permits the detailed composition of bile acids in feces in terms of both the individual bile acids present and their mode of conjugation in the original fecal sample. The extraction, purification, and isolation procedures have been evaluated using fecal samples containing endogenous radioactive bile acid metabolites and from the addition of radiolabeled standards to fecal homogenates. The applicability of the general procedure is illustrated with examples from the analysis of bile acids and sterols in the feces collected from normal healthy subjects, patients with chronic diarrhea, and an adult female Sprague-Dawley rat. The flexibility of the method, and the general problems encountered in the extraction, purification, and isolation of bile acids and related classes of compounds from feces for subsequent analysis of gas-liquid chromatography are discussed in detail.

Bile Acids and Salts↗