Three Japanese patients with lecithin: cholesterol acyltransferase (LCAT) deficiency, the offspring of a consanguineous marriage, are described. In addition to the characteristic clinical and laboratory findings of the disease, our patients had hitherto unreported manifestations, namely unconjugated hyperbilirubinemia, peripheral neuropathy and marked hypocholesterolemia. Although the mechanism of the unconjugated hyperbilirubinemia is not clear, the role of impaired hepatic bilirubin uridine-diphosphate-glucuronyl transferase activity combined with another unknown factor(s) was postulated. Non-random assortment was observed between LCAT deficiency and haptoglobin types, as previously reported. The discovery of Japanese patients with LCAT deficiency indicates that the distribution of this hereditary metabolic disorder is not confined to the Western hemisphere.

Adult↗

PubMed1978

Effects of thyroid-stimulating hormone on human thyroid carcinoma and adjacent normal tissue.

Effects of TSH on the adenylate cyclase-cAMP system and some parameters of intermediary metabolism were investigated in human thyroid carcinoma and adjacent normal thyroid tissue. Basal adenylate cyclase activity and cAMP concentrations were significantly higher in carcinomatous tissue. Basal [1-14C]glucose oxidation, 32Pi incorporation into phospholipids, and organification of iodide were similar in both tissues. Stimulation of cAMP by TSH was significantly greater in normal compared to carcinomatous tissue. In neither tissue was there a good correlation between TSH stimulation of adenylate cyclase activity and cAMP concentrations. The TSH stimulation of 32Pi incorporation into phospholipids by TSH was significantly greater in normal tissue. The mean effect of TSH on iodide organification and glucose oxidation was similar in normal and carcinomatous tissue. Although specific binding of TSH was demonstrated in both normal and carcinomatous tissue, it did not correlate very well with stimulation of adenylate cyclase activity. Hormones other than TSH also augmented adenylate cyclase activity in two of the carcinomas. In individual patients, the relative responsivity of carcinomatous tissue compared to normal was not always consistent when all of the metabolic parameters were considered.

Adenylyl Cyclases↗

PubMed1978

[Convulsions and monoamines].

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Animals↗

PubMed1977

5-(Tetradecyloxy)-2-furancarboxylic acid and related hypolipidemic fatty acid-like alkyloxyarylcarboxylic acids.

5-(Tetradecyloxy)-2-furancarboxylic acid (91, RMI 14514) was found to lower blood lipids and to inhibit fatty acid synthesis with minimal effects on liver weight and liver fat content. This fatty acid-like compound represents a new class of hypolipidemic agent; it is effective in rats and monkeys. The compound resulted from discovery of hypolipidemic activity in certain beta-keto esters, postulation and confirmation of the corresponding benzoic acids as active metabolites, and systematic exploration of the structure--activity relationships.

Animals↗

PubMed1976

Effects of adenosine and its derivatives on protein kinase activity of beef thyroid.

Effects of adenosine and some of its derivatives on beef protein kinase activity were investigated in vitro. Adenosine rapidly inhibited protein kinase activity in a dose-dependent manner. Significant inhibition occurred with 10 muM and half-maximal inhibition at 100 muM adenosine. Inhibition was almost complete with 5 mM adenosine. Inhibition was similar whether protein kinase activity was assayed with or without cyclic AMP. The inhibition by adenosine was reversed by increasing the concentration of ATP and Lineweaver-Burk analysis indicated that adenosine inhibition was competitive with ATP. Addition of adenosine deaminase to the incubation medium prevented the inhibition induced by adenosine. Intact 1 and N6 positions of adenosine were important for the inhibition since their modification was associated with loss of inhibition. Modification of the 8 position of adenosine decreased, but did not abolish, the inhibition. The 2 and 3 position of ribose did not seem to be critical since 2- and 3-deoxyadenosine produced inhibition similar to that of adenosine.

Adenosine↗

PubMed1976

(2-Piperidine)- and (2-pyrrolidine)ethanones and -ethanols as inhibitors of blood platelet aggregation.

(E)-4-[4-(Methylthio)phenyl]-1-(2-piperidinyl)-3-buten-2-one hydrochloride (44, RMI 14 133A) was found to inhibit ADP-induced aggregation of blood platelets. It was selected from a large series of (2-piperidinyl)- and (2-pyrrolidinyl)ethanones synthesized by a modified Schopf reaction from enolate magnesium salts of beta-keto acids and 2,3,4,5-tetrahydropyridine trimer or 3,4-dihydro-2H-pyrrole trimer, respectively. Evaluation of the compounds was carried out in vitro on human blood platelets. Structure-activity relationships are discussed. 44 also inhibited platelet aggregation ex vivo in guinea pigs. Subacute toxicity evaluation in dogs and guinea pigs showed it to have an unfavorable therapeutic ratio. 1-[4'-Chloro(1,1'-biphenyl)-4-yl-a1-2-(2-piperdinyl)ethanone hydrochloride (18, RMI 12436A) was found to lower serum cholesterol levles in rats with concurrent accumulation of (3beta)-cholesta-5,7-dien-3-ol, suggesting inhibition of 7-dehydrocholesterol delta7-reductase.

Adenosine Diphosphate↗

PubMed1975

Studies of thyroid-stimulating hormone binding to bovine thyroid plasma membranes.

131I-TSH prepared by the lactoperoxidase method was used to study the binding of hormone to bovine thyroid plasma membrane. Specific binding was obtained using as little as 0.12 mU/ml 131I-TSH. Half-maximal binding occurred with 17.1 plus or minus 3.5 mU/ml and saturation at approximately 40 mU/ml. Scatchard plot analysis revealed two classes of binding sites, with association constants of 1.1 plus or minus 0.06 x 10(8) M(-1) and 1.4 x 10(7) M(-1) for the high- and low-affinity sites, respectively. Binding of 131I-TSH was linearly related to the amount of thyroid plasma membrane protein. Other polypeptide hormones and prostaglandin E1 did not inhibit specific TSH binding. Identical results were obtained using two TSH preparations of different biologic specific activity. 12.5 mU/ml unlabeled TSH decreased 131I-TSH binding 50%, and 156 mU/ml caused complete inhibition. After equilibrium of 131I-TSH binding was established, maximal displacement was achieved by 120 min using about 300 mU/ml TSH. However, only about one-half of the 131I-TSH was displaced. Although GTP potentiated the stimulation of adenylate cyclase by TSH, it inhibited binding of 131I-TSH. Binding of TSH correlated very well with activation of adenylate cyclase.

Adenylyl Cyclases↗

PubMed1974