The development of bile acid synthesis.
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Biomedical subjects
Publications and source records attributed to R Lester.
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A case of an adult with chronic active hepatitis associated with giant multinucleated liver cells is presented. The giant liver cells in this case are widespread and the picture resembles neonatal hepatitis. The morphology, pathogenesis, and epidemiology of giant hepatocytes found in human neonates and adults and in experimental animals is discussed. Because the proliferative phase of giant hepatic cells is transient, this reaction may be more common than generally believed.
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A new technique has been developed in which mammalian fetal liver can be maintained in organ culture for prolonged periods with intact structure and function. Near-term rat fetal liver explants were incubated in vitro for periods of up to 3 wk with preservation of normal cellular morphology and intercellular (organ) relationships. [14C]cholate was incorporated into tissue and medium conjugates at a constant rate during 21 days in vitro. During a 24-h incubation with radioactively labeled cholic acid, bile acid conjugates accumulated in tissues to a maximum value by 6 h and maintained this value through 24 h. During the same 24-h incubation with [14C]cholate, conjugates were secreted into the medium at a constant rate. Addition of 8 X 10(-4) M taurine to the medium during a 4-day incubation produced a threefold enhancement in the rate of conjugate formation in tissues and medium. Enhanced conjugation in the presence of additional taurine was due almost entirely to increased taurocholate formation and no significant difference was observed in the amount of glycocholate formed. Exposure of explants to 3.6 X 10(-4) M cycloheximide for prolonged periods resulted in inhibition of conjugate formation, but when this concentration of cycloheximide was maintained for only 24 h a significantly (P less than 0.001) increased rate of conjugate formation was observed. The results indicate that metabolic processes in the organ-culture system are in a state of dynamic equilibrium and that morphologic integrity and specific hepatocytic function are maintained after 21 days in vitro. Preferential taurocholate formation was demonstrated in rat fetal liver, and the data suggest that glycine and taurine interact with separate enzymatic systems in bile acid conjugation. The possible mechanisms that mediate the effect of cycloheximide are discussed.
Both as the result of liver disease and of alcoholism per se, chronic alcoholics develop infertility, sterility, gonadal atrophy, hypoandrogenization, and feminization. The hypothalamic-pituitary abnormalities associated with alcoholism include hyperprolactenemia-increased estrogen-stimulated neurophysin levels, suppressed secretion of plasma gonadotropins, and loss of gonadotropin reserve. Several of the possible mechanisms potentially responsible for the development of these endocrine abnormalities have been discussed. The rational for suspecting that alcohol might interfere with either vitamin A metabolism of alter the redox state of the testes, thus affecting germ cell proliferation and steroidogenesis, has been presented. A possible mechanism for the sexual changes observed in chronic alcoholic men has been proposed. Much work remains to be done in this area before a complete understanding of the pathogenesis of these phenomena is obtained. The omission of any consideration of the effects of alcohol on sexual function in women is an admission of gross ignorance greatly in need of rectification. The necessity for couching a description of even the natural history of the syndrome in alcoholic men in conditional terms is a reflection of the limited state of the art. Nevertheless, it behooves the gastroenterologist, who is frequently called upon to be the primary physician for alcoholic men, to keep abreast of the nongastrointestinal medical consequences of alcohol addiction so that they can be recognized early and incorporated into long range medical planning designed to care for the chronic alcoholic patient.
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Although crustacean tissue cholesterol content is high, Crustacea, like other arthropods; are incapable of cholesterol synthesis, and presumably are dependent for maintaining tissue cholesterol stores on the intestinal absorption of ingested sterol. A detergent, N-(N-dodecanoylsarcosyl)taurine, representative of a set of detergents synthesized by the crustacean hepatopancreas and secreted into the intestine, is capable of efficient cholesterol solubilization, and thus of promoting sterol absorption.
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The feminization frequently observed in men with alcoholic liver disease has not been satisfactorily explained by existing reports. We have measured plasma estrone, prolactin, estrogen-stimulated neuorphysin, and sex steroid-binding globulin concentrations in 50 men with chronic alcoholism and varying degrees of alcoholic liver disease in an effort to further elucidate possible hormonal mechanisms responsible for the observed feminization. Plasma concentrations of each of these parameters were at least two-fold elevated (p smaller than or equal to 0.01) when compared to values obtained for the same steroid or protein in plasma obtained from normal men. The plasma concentrations of estrone and prolactin in men studied with synecomastia were significantly greater (p smaller than or equal to 0.01 and p smaller than or equal to 0.05, respectively) than were the concentrations of these two hormones in those without this physical sign. Similarly, those men with spider angiomata had significantly greater (p smaller than or equal to 0.01) plasma estrone levels than did the men without this cutaneous vascular abnormality. These significant hormone elevations may contribute to the pathogenesis of feminization so frequently observed in chronic alcoholic men.
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Bile salt synthesis and bile salt pool size were determined by isotope dilution in two groups of healthy premature infants, utilizing nonradioactive deuterium-labeled bile salts. All 9 infants were between 32 and 36 weeks of gestation; however, in one group (4 infants), the mothers had received either dexamethasone or phenobarbital prior to delivery. The total bile salt pool averaged 20 mg for the infants of untreated mothers and 79 mg for the infants of treated mothers; similarly, the bile salt synthesis of 8 mg per day in the untreated group was increased to 27 mg per day for the treated group. Expressed per sq m of body surface, the cholic acid pool for the treated group was 321 mg per sq m, and the cholic acid synthesis rate equaled 98 mg per sq m per day; values equal to those for full term infants and nearly 4 times those for the untreated prematures. The intraduodenal bile salt concentrations obtained during meals were also low in the untreated group, equaling 1.2 mM as compared to 5.3 mM for the treated group. The reductions of bile salt pool size, synthesis, and intestinal concentration establish that the functional maturity of the liver, and possibly the gastrointestinal tract, is reduced in premature infants. The results further suggest that this maturity may be dramatically influenced by medications administered to the mother prior to delivery.
Elucidation of mechanisms involved in the hypogonadism and feminization observed in chronic alcoholic men requires the development of an experimental animals model system. Such an animal system should be inducible with ethanol feeding and should duplicate endocrine changes known to occur in chronic alcoholic men. We report such an animal model system. Animals fed a diet with ethanol accounting for 36% of total calories develop significant testicular, prostatic, and seminal vesicle atrophy (P less than 0.01) and greatly reduced plasma testosterone levels (P less than 0.01). Animals fed a similar diet with sucrose isocalorically substituted for ethanol do not. Testicular, prostatic, and seminal vesicular mass relative to body mass and plasma testosterone levels in these isocaloric control animals do not vary significantly from those obtained for age-matched control animals fed an ad libitum rat chow diet. These findings indicate that the caloric deprivation associated with chronic ethanol ingestion is not responsible for gonadal injury and atrophy of the sex steroid-sensitive tissues in the alcohol-fed animals. This animal model provides a useful means of directly examining perturbation in gonadal function that occurs in man as a consequence of chronic ethanol ingestion and confirms our previous data which suggest that ethanol is a primary testicular toxin.
Fetal bile salt metabolism was assessed by the intravenous infusion of e114C]cholate into 6 monkey fetuses. The placental transfer, fetal plasma clearance, and fetal hepatic excretion of the administered radiolabeled bile salt were measured. Placental transfer averaged 30% of the injected dose, while biliary excretion averaged 36%. Of the amount excreted by the fetal liver, 78% was in the form of [14C]taurocholate. The findings suggest that bile salt metabolic and excretory mechanisms are undergoing developmental maturation at birth.
Vitanin A (retinol) is essential for spermatogenesis. Alcohol dehydrogenase, the enzyme responsible for ethanol metabolism, is also required for the conversion of retinol to bioactive retinal at the end organ site. Ethanol inhibits the oxidation of retinol by testicular homogenates containing alcohol dehydrogenase. Thus, a possible biochemnical mechanism for the sterility of chronic alcoholics is identified.