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Query: UMLS:C0432222 (SEM)
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Severe combined immunodeficient (SCID) mice were injected with peripheral blood mononuclear cells (PBMC) from normal individuals and 14 out of 18 had detectable serum human (h) IgG (maximum levels providing a mean +/- SEM 934 +/- 213 micrograms/ml) and IgM (253 +/- 93 micrograms/ml) at 3-6 weeks after transplantation. Serum human immunoglobulin levels were maximum 6-12 weeks after transplantation and declined to low levels over the subsequent 5 months. Human B cells constituted up to 10% and human T cells up to 40% of cells in the peripheral circulation and spleens of these animals 2-3 weeks after transplantation, PBMC, or intrathyroidal (IT) lymphocytes, from 6 patients with Graves' disease and high serum levels of thyroid autoantibodies were transplanted into 30 SCID mice (Graves' SCID-hu). Although serum human immunoglobulins were observed in only low amounts in the animals receiving IT lymphocytes (n = 4), increased levels of hIgG or hIgM were more easily detectable in 19 Graves' SCID-hu mice that received PBMC. The Graves' SCID-hu mice had significantly lower mean levels of hIgG and hIgM than those observed following transplantation of normal PBMC (mean maximum 328 +/- 113 and 32 +/- 21 micrograms/ml, respectively). Six of these 19 mice had detectable human autoantibody to thyroid peroxidase (TPO, as microsomal antigen) between 3 and 8 weeks after transplantation, with titers ranging from 0.05 to 0.39 (normal SCID-hu serum less than 0.02 ELISA Index). No abnormal thyroid hormone (T4 and T3) levels or thyroiditis was seen when compared to normal SCID-hu mice. Immunization of reconstituted SCID mice with recombinant immunoactive human TPO antigen failed to initiate anti-TPO in normal PBMC-treated mice nor did it increase the titer of human anti-TPO in the anti-TPO positive animals. In conclusion we successfully established human thyroid autoantibody secretion in the SCID-hu mouse and characterized the transient nature of the model. Further studies will be required to achieve successful antigen presentation in this system.
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PMID:The SCID-hu mouse and thyroid autoimmunity: characterization of human thyroid autoantibody secretion. 207 May 73

NAD(P)H:quinone oxidoreductase (EC 1.6.99.2; DT-diaphorase) was present in the liver of 18- and 19-day-old chick embryos as assayed both by reduction of resorufin and by the more traditional assay, reduction of 2,6-dichlorophenolindophenol (DCPIP). Both reductions had the classic characteristics of DT-diaphorase: they were equally supported by NADPH and NADH and almost entirely inhibited by dicumarol. Chick embryo liver DT-diaphorase was entirely cytosolic. It was undetectable in the microsomal and mitochondrial fractions. Chick embryo liver cytosol and mitochondrial fractions contained an enzyme oxidizer of resorufin but not of DCPIP. The Km for NADPH for resorufin reductase was an order of magnitude higher in chick embryo than in rat or guinea pig cytosol (1 mM vs 0.1 mM). Resorufin reductase activity was higher for chick embryo than for rat or guinea pig cytosols: Vmax (nmol resorufin reduced per mg cytosolic protein per min +/- SEM) 355 +/- 28 for chick embryo, 159 +/- 10 for guinea pig and 68 +/- 28 for rat. The Vmax for DCPIP reduction was also twice as high in chick embryo as rat liver cytosol. In the chick embryo, 7 days after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 6.4 micrograms/kg egg (1 nmol/egg) mortality was increased 2.4-fold, hepatic DT-diaphorase 1.3-fold, and 7-ethoxyresorufin deethylase (7-EROD) 72-fold over control levels. At 32 micrograms/kg, mortality was increased 4.2-fold, DT-diaphorase 2.3-fold and 7-EROD 100-fold. In the guinea pig, 5 days after treatment with TCDD at 10 micrograms/kg, TCDD toxicity was also evident (loss of body weight and thymus weight); there was no change in DT-diaphorase as measured by resorufin reduction, confirming by a different assay the observation of Beatty and Neal (Biochem Pharmacol 27: 505-510, 1978) that TCDD does not induce DT-diaphorase in guinea pig liver, and 7-EROD was increased 8-fold. In contrast, in the rat, 7 days after exposure to TCDD at 10 micrograms/kg, there was no evidence of toxicity, DT-diaphorase was increased close to 7-fold and 7-EROD, 100-fold. The results demonstrate that avian liver contains DT-diaphorase and show that the extent to which DT-diaphorase is part of the pleiotypic response of the liver to an Ah (aryl hydrocarbon) receptor ligand is species dependent. They also suggest that DT-diaphorase induction and TCDD toxicity may be inversely related. The possibility that DT-diaphorase protects against TCDD toxicity and participates in species differences in sensitivity to TCDD toxicity warrants further investigation.
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PMID:NAD(P)H: quinone oxidoreductase (DT-diaphorase) in chick embryo liver. Comparison to activity in rat and guinea pig liver and differences in co-induction with 7-ethoxyresorufin deethylase by 2,3,7,8-tetrachlorodibenzo-p-dioxin. 210 32

Human chorion and decidua use pregnenolone sulfate (P5S) and dehydroepiandrosterone sulfate (DHAS) as substrates for local estrogen and progesterone synthesis. We hypothesized that the local estrogen/progesterone ratio may influence contractility of the adjacent myometrium and hence effect the timing of parturition. Thus, we studied steroid sulfohydrolase activity for P5S in these tissues and investigated the potential interaction of other steroids on the rates of hydrolysis of P5S and DHAS. The enzyme was present in both tissues, predominantly in the microsomal fraction. With P5S as substrate, the Michaelis-Menten constant (Km) was similar in chorion (1.3 +/- 0.2 mumol/L, mean +/- SEM) and decidua (0.9 +/- 0.1 mumol/L) but the maximum velocity (Vmax) was significantly greater in chorion (2.6 +/- 0.4 vs. 1.1 +/- 0.3 nmol/mg protein/15 min, P less than 0.05). In both tissues there was a tendency towards greater activity in tissues obtained before labor compared to tissues obtained after spontaneous labor onset. Using either DHAS or P5S as substrate, there was significant inhibition of sulfohydrolase activity by other steroids at concentrations similar to those in late pregnancy fetal and maternal plasma. In microsomal preparations using DHAS as substrate, activity was inhibited by equimolar concentrations of estrone sulfate (E1S, by 38 +/- 2%), P5S (by 74 +/- 2%), and cholesterol sulfate (C27S, by 38 +/- 3%). With P5S as substrate, equimolar concentrations of E1S, DHAS, and C27S caused inhibition of sulfohydrolase activity by 19 +/- 5%, 16 +/- 4%, and 18 +/- 2%, respectively. These inhibitory effects also were observed using a tissue explant system with intact cells. In kinetic inhibition studies using DHAS as substrate, E1S and P5S were competitive inhibitors with inhibition constants (Ki) of 4.8 +/- 1.3 and 0.7 +/- 0.1 mumol/L, respectively. Using P5S as substrate, E1S and DHAS also were competitive inhibitors with Ki values of 8.2 +/- 2.1 and 9.6 +/- 1.2 mumol/L, respectively. For both substrates, the pattern of inhibition by C27S was complex. Preliminary experiments to distinguish, on the basis of differing physical-chemical properties, separate enzymes for different substrates were inconclusive. We conclude that human chorion and decidua can hydrolyze several steroid sulfoconjugates and this activity may regulate local estrogen and progesterone synthesis. There are significant interactions among steroid sulfoconjugates in regulating this activity. These activities may be important components of a paracrine system that determines myometrial contractility and the timing of parturition.
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PMID:Steroid sulfohydrolase in human chorion and decidua: studies using pregnenolone sulfate and dehydroepiandrosterone sulfate as substrate. 214 Aug 34

Glucose transport is decreased in skeletal muscle and adipose tissues of obese, hyperglycemic, insulin-resistant animals. Here we have characterized the glucose transporter(s) in muscle and adipose tissues from normal and obese mice, and we have studied the effect of a treatment with the thermogenic agent BRL 26830A. Glucose transporters were examined in crude tissue membrane fractions (microsomal + plasma membranes) by Western blot analysis using antipeptide antibodies specific for the erythroid (Glut 1) or muscle/fat (Glut 4) glucose transporters. In these insulin sensitive tissues, only Glut 4 was detected. In membranes from obese animals, the Glut 4 number was decreased by 40% +/- 4% in brown adipose tissue (mean +/- SEM of 9 preparations, P less than 0.001), whether the results were expressed per total tissue or per mg of protein. By contrast, Glut 4 number was unchanged in skeletal muscle. In white adipose tissue of obese animals, Glut 4 number per total fat pad was increased. However, due to the enlarged fat pad size, Glut 4 content was diminished when expressed per mg of white adipose tissue membrane protein in obese compared to lean animals. After a 18 day-treatment with BRL 26830A (1 or 2 mg/kg.day), glycemia of obese mice, which was slightly elevated compared to lean animals, was normalized, while insulinemia remained markedly above control values. In brown adipose tissue, the total number of Glut 4 returned to normal at 1 mg of the drug, or increased by 63% +/- 14% at 2 mg. Since membrane protein content was increased by the treatment, when results were expressed per mg of membrane protein, Glut 4 was similar in lean and BRL 26830A (1 or 2 mg) treated obese mice. BRL 26830A treatment did not modify Glut 4 in skeletal muscle, and it increased Glut 4 number in white adipose tissue in a dose-dependent manner. In conclusion, in obese mice, the glucose transporter number was reduced mainly in brown adipose tissue, a defect which could contribute to the hyperglycemic syndrome. Treatment with the thermogenic agent BRL 26830A normalized in parallel glycemia and glucose transporter number in brown adipose tissue, suggesting that this tissue could play a role in glucose homeostasis in rodents.
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PMID:Glucose transporter in insulin sensitive tissues of lean and obese mice. Effect of the thermogenic agent BRL 26830A. 224 21

The regulation of transepithelial water permeability in toad urinary bladder is believed to involve a cycling of endocytic vesicles containing water transporters between an intracellular compartment and the cell luminal membrane. Endocytic vesicles arising from luminal membrane were labeled selectively in the intact toad bladder with the impermeant fluid-phase markers 6-carboxyfluorescein (6CF) or fluorescein-dextran. A microsomal preparation containing labeled endocytic vesicles was prepared by cell scraping, homogenization, and differential centrifugation. Osmotic water permeability was measured by a stopped-flow fluorescence technique in which microsomes containing 50 mM mannitol, 5 mM K phosphate, pH 8.5 were subject to a 60-mM inwardly directed gradient of sucrose; the time course of endosome volume, representing osmotic water transport, was inferred from the time course of fluorescence self-quenching. Endocytic vesicles were prepared from toad bladders with hypoosmotic lumen solution treated with (group A) or without (group B) serosal vasopressin at 23 degrees C, and bladders in which endocytosis was inhibited by treatment with vasopressin at 0-2 degrees C (group C), or with vasopressin plus sodium azide at 23 degrees C (group D). Stopped-flow results in all four groups showed a slow rate of 6CF fluorescence decrease (time constants 1.0-1.7 s for exponential fit) indicating a component of nonendocytic 6CF entrapment into sealed vesicles. However, in vesicles from group A only, there was a very rapid 6CF fluorescence decrease (time constant 9.6 +/- 0.2 ms, SEM, 18 separate preparations) with an osmotic water permeability coefficient (Pf) of greater than 0.1 cm/s (18 degrees C) and activation energy of 3.9 +/- 0.8 kcal/mol (16 kJ/mol). Pf was inhibited reversibly by greater than 60% by 1 mM HgCl2. The rapid fluorescence decrease was absent in vesicles in groups B, C, and D. These results demonstrate the presence of functional water transporters in vasopressin-induced endocytic vesicles from toad bladder, supporting the hypothesis that water channels are cycled to and from the luminal membrane and providing a functional marker for the vasopressin-sensitive water channel. The calculated Pf in the vasopressin-induced endocytic vesicles is the highest Pf reported for any biological or artificial membrane.
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PMID:Very high water permeability in vasopressin-induced endocytic vesicles from toad urinary bladder. 251 41

Steroid sulfatase (STS) activity was studied in the Long-Evans rat testis. The rate of dehydroepiandrosterone sulfate (DHA-S) hydrolysis determined in whole testis homogenates was low compared to that of the corresponding microsomal fractions, which was, in contrast, as high as that expressed in homogenates from purified Leydig cells. Such an increment in STS activity between total homogenates and the corresponding microsomes was not observed for the seminiferous tubules. The STS affinity reported for total testicular microsomes (Km = 3.47 +/- 0.54 microM; mean +/- SEM) was of the same magnitude as that previously reported for Leydig cells, but was about 3 times higher than that measured for whole testis homogenate (Km = 10.11 +/- 0.92 microM). In vivo hCG treatment decreased the STS affinity in total testicular microsomes without affecting this kinetic parameter in whole testis homogenate. These data suggest that the steroid sulfatase expressed in total testicular microsomes (activity and regulation by hCG) could be considered as a good index of Leydig cell STS activity.
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PMID:Steroid sulfatase activity in homogenates, microsomes and purified Leydig cells from adult rat testis. 253 91

A sonographic grey scale (gs) analysis of the thyroid gland was retrospectively (1985-1986) performed in 248 patients with normal sized thyroid glands or "diffuse" thyroid diseases. During the examination the physical parameters for gain, far and near gain were constant. The normal value (means +/- 2 s) in 95 patients with normal sized and euthyroid thyroid glands was lower in females (gs: 14 +/- 4) than in males (gs: 16 +/- 6), children had obviously lower patterns (gs: 7.1), adolescents had low normal patterns (gs: 11). The echogenicity increased with increasing thyroid volumes. In patients with autoimmune thyroid diseases an obvious low echogenicity could be demonstrated (Hashimoto's thyroiditis, gs-SEM: 8.3 +/- 1.5; Grave's disease, gs-SEM: 6.7 +/- 1.2) (SEM = standard error of the mean). Euthyroid patients with microsomal antibody titers showed low normal grey scale patterns (gs: 10.9 +/- 3). In patients after subtotal thyroidectomy the grey scale pattern decreased with decreasing volume of the residual thyroid gland. The grey scale pattern increased years after surgery. The subjective grading of the grey scale pattern was different from the quantitatively measured pattern in 18% of the patients with glands of normal size.
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PMID:[The importance of quantitative grey-scale analysis of the sonogram in "diffuse" thyroid diseases]. 253 99

The present work tested the hypothesis that portal venous bile acids regulate the activity of the cholesterol 7 alpha-hydroxylase and studied the influence of hepatic microsomal free cholesterol concentration on the enzyme activity. Operative liver biopsies and samples of portal venous blood were obtained from a total of 61 patients with gallstones who were undergoing cholecystectomy. Fifteen of the patients were treated with cholestyramine (16 g/day) for 2-3 wk before operation and 23 patients with chenodeoxycholic acid (15 mg/kg.day) or ursodeoxycholic acid (15 mg/kg.day) for 3-4 wk before operation. Highly accurate methods based on isotope dilution-mass spectrometry were used for assay of the cholesterol 7 alpha-hydroxylase activity, the concentration of free cholesterol in the microsomes, and the levels of individual bile acids in portal venous blood. Cholestyramine treatment increased the cholesterol 7 alpha-hydroxylase activity about sixfold, from 7.6 +/- 1.1 (mean +/- SEM) to 45.7 +/- 6.7 pmol/min.mg protein. Administration of chenodeoxycholic acid reduced the enzyme activity considerably to 1.0 +/- 0.3 pmol/min.mg protein, whereas ursodeoxycholic acid did not significantly affect the enzyme activity (7.9 +/- 2.2 pmol/min.mg protein). The concentration of microsomal free cholesterol remained essentially unchanged in spite of a 45-fold variation in enzyme activity. There was a negative correlation between the absolute as well as the relative concentration of chenodeoxycholic acid in portal blood and the activity of the cholesterol 7 alpha-hydroxylase, whereas there was no correlation between the total concentration of bile acids and the enzyme activity. It is concluded that the composition of individual bile acids may be more important than the total concentration of bile acids in the portal vein for the regulation of the cholesterol 7 alpha-hydroxylase activity in humans. It is further concluded that chenodeoxycholic acid is a considerably stronger suppressor of bile acid synthesis than ursodeoxycholic acid.
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PMID:Bile acid synthesis in humans: regulation of hepatic microsomal cholesterol 7 alpha-hydroxylase activity. 258 15

The aim of the present study was to characterize the acyl-coenzyme A: cholesterol acyltransferase (ACAT) activity in human liver microsomes. Liver biopsies were obtained from patients undergoing elective cholecystectomy under highly standardized conditions. In 34 patients the enzyme activity of the microsomal fraction averaged 6.6 +/- 0.7 (mean +/- SEM) pmol.min-1.mg protein-1 in the absence of exogenous cholesterol. Freezing of the liver biopsy in liquid nitrogen increased the enzyme activity five- to sixfold. Similarly, freezing of the microsomal fraction prepared from unfrozen liver tissue increased the enzyme activity about twofold. These results may help to explain previous disparate results reported in the literature. The enhanced ACAT activity obtained by freezing was at least partly explained by a transfer of unesterified cholesterol to the microsomal fraction and possibly also by making the substrate(s) more available to the enzyme. Preincubation of the microsomal fraction, prepared from unfrozen liver tissue, with unlabeled cholesterol increased the enzyme activity about fivefold. This finding indicates that hepatic ACAT in humans can also utilize exogenous cholesterol as substrate. Addition of cholesterol to frozen microsomes prepared from unfrozen liver tissue increased the ACAT activity two- to threefold, whereas addition of cholesterol to microsomes prepared from frozen liver tissue did not further increase the enzyme activity. No evidence supporting the concept that ACAT is activated-inactivated by phosphorylation-dephosphorylation could be obtained by assaying the enzyme under conditions similar to those during which the human HMG-CoA reductase is inactivated-activated.
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PMID:Studies on acyl-coenzyme A: cholesterol acyltransferase activity in human liver microsomes. 276 May 47

Ketoconazole, an orally active antifungal drug, is known to inhibit testicular androgen production both in vitro and in vivo. The aim of the present study was to examine the effect of ketoconazole and 13 other imidazole drugs on rat testicular microsomal 17 alpha-hydroxylase, 17,20-lyase, 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) and 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR). The order of decreasing inhibitory effect (determined from Ki values) on 17 alpha-hydroxylase (substrate [3H]progesterone; Km = 89 +/- 0.65 nmol/l; SEM, n = 8) was bifonazole (Ki = 86 +/- 3.3 nmol/l; SEM, n = 4) greater than ketoconazole (160 +/- 4.92) greater than clotrimazole (170 +/- 5.81) greater than miconazole (599 +/- 7.22) greater than econazole (688 +/- 6.98) greater than tioconazole (901 +/- 1.71) greater than isoconazole (1090 +/- 6.96) and on 17,20-lyase (substrate, [3H]17 alpha-hydroxyprogesterone; Km = 250 +/- 0.75 nmol/l; SEM, n = 8) was bifonazole (56.5 +/- 3.4) greater than clotrimazole (81.5 +/- 3.1) greater than ketoconazole (84 +/- 3.5) greater than miconazole (243 +/- 6.3) greater than econazole (325 +/- 5.1) greater than tioconazole (505 +/- 5.2) greater than isoconazole (610 +/- 6.34). However, these imidazole drugs did not inhibit the 3 beta-HSD-I or 17 beta-HSOR activities. A common structural feature of the imidazole drugs having an inhibitory effect was the presence of one or more aromatic rings on the imidazole side chain. In contrast, the imidazole drugs having the imidazole ring fused to a benezene ring, i.e. benzimidazoles (astemizole, mebendazole, thiabendazole) and those having an aliphatic side chain on the N-1 of the imidazole ring (carbimazole, metronidazole, nimorazole, tinidazole) did not inhibit 17 alpha-hydroxylase, 3 beta-HSD-I or 17 beta-HSOR enzyme activities. However some did inhibit 17,20-lyase activity but only at high concentrations. The results of the present study suggest that some imidazole drugs may be useful in clinical situations requiring the suppression of androgen production, for example in the treatment of hormone-dependent prostatic cancer.
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PMID:Inhibition of testicular 17 alpha-hydroxylase and 17,20-lyase but not 3 beta-hydroxysteroid dehydrogenase-isomerase or 17 beta-hydroxysteroid oxidoreductase by ketoconazole and other imidazole drugs. 282 31


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