Detection of IQ-type heterocyclic amines in dialysis fluid of uremic patients treated by peritoneal dialysis.
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Adult↗
Biomedical subjects
S Manabe
Publications and source records attributed to S Manabe.
Presence of 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx) in dialysate from patients with uremia.
MeIQx (2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline), a carcinogenic heterocyclic amine, was found to be present in dialysis fluid of 8 patients with uremia, but not in fresh dialysis fluid before dialysis treatment. Concentrations of MeIQx in dialysates ranged from 14 to 32 pM. The mean absolute contents of MeIQx in dialysates (6 to 40 liters) was 334 p mole. These results indicate that the carcinogenic heterocyclic amine is present in the plasma of all patients with uremia.
Adult↗
Miconazole inhibition of platelet aggregation by inhibiting cyclooxygenase.
Platelet dysfunction was found in rabbits to which a dose of miconazole nitrate (1.6 mg/kg body wt) therapeutic for human subjects had been given intravenously. The present experiments were conducted to elucidate the mechanism of inhibitory effects of miconazole on platelet function. After administration of a single dose of miconazole, rabbit platelet aggregation induced by collagen and sodium arachidonate was inhibited significantly for approximately 24 hr. On the other hand, hypertriglycemia, one of the major side effects of this drug, was not seen during 2 days of observations, nor were any other outstanding manifestations observed. In in vitro experiments, miconazole nitrate (10 microM) also significantly inhibited rabbit and human platelet aggregation (P less than 0.01). Biochemical analyses revealed that the stimulant-induced formation of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2), metabolites via cyclooxygenase, was inhibited by miconazole nitrate in both human and rabbit platelets in vitro. PGE2 production was decreased dose-dependently with the increase of miconazole concentration (10 to 100 microM), and the decrease was in parallel with a decrease of TXB2 production. In addition, malondialdehyde (MDA) production of human and rabbit platelets induced by exogenous arachidonate and collagen was also inhibited significantly by miconazole. Chromatographic studies showed that the amount of 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE), a metabolite via lipoxygenase, was increased markedly in accordance with the miconazole-induced decrease of TXB2 and 12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) formation in both human and rabbit platelets. These results indicate that miconazole nitrate inhibits platelet cyclooxygenase, without affecting the stimulant-induced release of arachidonic acid from platelet phospholipids. Use of this drug in the treatment of systemic fungal infection appears to be increasing. Careful attention should be paid to the inhibitory effects of miconazole on platelet function, especially in the case of intravenous treatment.
Adenosine Diphosphate↗
Epidural migration of extruded cervical disc and its surgical treatment.
Twenty-two patients with epidural migration of cervical disc fragments were reviewed. Disc sequestrations can migrate to the anterior, posterior, and lateral aspects of the spinal canal and are divided into four types according to their localizations. Those migrating to the anterior or posterior surface of the spinal canal, causing myelopathy, were removed through either an anterior or posterior route. Removal of lateral sequestration by uncoforaminotomy provided full recovery for all patients with radiculopathy and drop-attacks. The number of disc sequestrations was not always one: three fragments were present in three patients and two fragments in five patients. Various routes combined with other approaches were indicated to eliminate completely the freely migrating disc sequestra.
Cervical Vertebrae↗
[Toxicity assessments of chemical substances using primary culture of rat hepatocytes].
A primary hepatocyte culture was used as a model system to assess the toxicity of various chemical substances. Chemical substances tested in this experiment included 14 kinds of organic solvents, arsenic acid and N-nitrosodiumethylamine, most of which are known as hepatotoxic materials. Enzyme (GPT and LDH) leakage and albumin secreted from the hepatocytes to culture medium were measured to evaluate the cell damage after exposure to the chemical substances at various concentrations for 3 d. Cell counts and protein contents before and after exposure to the chemical substances were also measured during the course of these experiments. The extent of LDH leakage from hepatocytes was parallel to that of GPT leakage after exposure to the chemicals. Albumin secreted from the hepatocytes in the culture medium evidently decreased at concentrations of the chemicals which increased the enzyme leakage. Viable cell counts were significantly decreased by chemicals that increased the enzyme leakage, although the cell protein contents were not significantly affected. The minimum concentration of the chemicals at which enzyme leakage from hepatocytes was significantly increased was defined as the lowest toxic concentration (TCL0). Judging from TCL0 values, the degree of toxicity in these chemicals seems to be almost identical to the degree of in vivo hepatotoxicity reported previously. We, furthermore, observed that there is a positive correlation (r = 0.780, p less than 0.01) between PT50 calculated by the LD50 value reported previously and -Log magnitude of TCL0.(ABSTRACT TRUNCATED AT 250 WORDS)
Alanine Transaminase↗
[Protein C dynamics in peripheral arterial occlusive diseases and myocardial infarction: association of homozygous protein C deficiency with heterozygous dysplasminogenemia found among patients with deep vein thrombosis].
Protein C(PC) is the zymogen of a serine protease which regulates blood coagulation by inactivating activated blood coagulation factors V and VIII. We investigated the plasma level of PC in patients with deep vein thrombosis (DVT, n = 50), Buerger's disease (n = 34), arteriosclerosis obliterans (n = 37) and myocardial infarction (n = 17). PC in plasma was determined by rocket immunoelectrophoresis using a monospecific anti-PC antiserum raised in rabbits. Our study indicated that only in DVT the level of PC was decreased in comparison with the normal control (p less than 0.05). This decrease may be accounted for by increased utilization of PC for the regulation of continuously activated blood coagulation mechanism possibly ongoing in patients with DVT. On the other hand, among the patients with the DVT, we found a homozygous PC deficiency combined with a heterozygous dysplasminogenemia in a 22-year old male who had been suffering from recurrent venous thrombosis since the age of 14. Although the homozygous form of PC deficiency has been reported to be closely associated with fatal thrombotic disorders including purpura furminans during the neonatal period, the patient reported here had surprisingly survived the neonatal period and the childhood without any clinical manifestation relevant to thrombosis.
Adult↗
[Congenital abnormalities related to coagulation and the fibrinolytic system in patients with vein thrombosis of the lower extremities].
Plasma concentrations of antithrombin III (AT III), plasminogen (Plg), and protein C (PC) were assayed in 28 patients with venous thrombosis of lower extremities without distinct underlying disorders. Three abnormalities were found in 5 cases (17.8%) in relation to coagulation and fibrinolytic system (3 with congenital AT III deficiency, one each with dysplasminogenemia and congenital PC deficiency). In the patients with either one of these abnormalities, characteristic features of thrombosis are summarized as follows; 1. early onset of clinical symptoms. 2. high frequency of superficial vein thrombosis. 3. high recurrence rate. 4. high frequency of pulmonary embolism.
Adolescent↗
Hereditary tyrosinemia. Formation of succinylacetone-amino acid adducts.
Succinylacetone (SA) (4,6-dioxoheptanoic acid) is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumaryl acetoacetate hydrolase activity. Patients with this disease are associated with a number of abnormalities, including aminoaciduria, proteinuria, liver failure, commonly hepatoma, and decreased GSH concentration in the liver. In the course of our studies of tyrosinemia, we found that the urine of patients with this disorder contains material(s) that absorbs light at 315 nm. We investigated the nature of the 315 nm material in detail. SA was found to react with amino acids and protein nonenzymatically, to form stable adducts at physiological temperature and pH. All SA adducts with amino acids and/or proteins exhibited an absorption peak at 315 nm. Although all amino acids reacted with SA, the most reactive amino acid was lysine (Lys), followed, in order, by glycine, methionine, phenylalanine, serine, alanine, and glutamine. SA-adducts were unstable at pH below 6, while they were made considerably more stable after reduction with NaBH4, suggesting that SA forms an adduct via Schiff base formation. High-performance liquid chromatography (HPLC) analysis of urines from patients with tyrosinemia revealed the existence of SA-glycine, SA-methionine, SA-tyrosine, and SA-phenylalanine. After digestion of urines with proteinase K, three more HPLC peaks appeared, which all corresponded to SA-Lys adducts. TLC analysis of SA-Lys showed that SA-Lys could form as many as seven different adducts. No SA-adduct peaks were observed in HPLC in urines from normal subjects, patients with other forms of aminoaciduria, or patients with the nephrotic syndrome. In addition to amino acids and proteins, SA reacted with reduced glutathione (GSH) and formed a stable adduct. These findings suggest that SA adduct formation with amino acids, GSH, and proteins is a significant process occurring in tyrosinemia, and may account for certain of the pathologic findings in this hereditary disorder.
Amino Acid Metabolism, Inborn Errors↗
Homozygous protein C deficiency combined with heterozygous dysplasminogenemia found in a 21-year-old thrombophilic male.
A congenital, probably homozygous deficiency of protein C combined with a heterozygous molecular abnormality of plasminogen was found in a 21-year-old male who had been suffering from recurrent venous thrombosis since the age of 14. Although the homozygous deficiency of protein C has been reported to be closely associated with fatal purpura fulminans or severe and massive thrombotic diseases during the neonatal period, the patient had survived the neonatal period without any clinical manifestations relevant to thrombosis. The patient apparently inherited the genetic abnormality of protein C deficiency from both of his parents and that of abnormal plasminogen from his father.
Adult↗
Fibrinogen Kawaguchi: an abnormal fibrinogen characterized by defective release of fibrinopeptide A.
A congenital dysfibrinogenemia was found in a 32-year-old asymptomatic female and her immediate family. The propositus, apparently a heterozygote for the abnormality, characteristically showed defective release of fibrinopeptide A from half of her fibrinogen molecules. No fibrinopeptide A was cleaved off from the isolated abnormal molecule by thrombin or snake venoms (Reptilase and Ancrod) as evidenced by radioimmunoassay, high performance liquid chromatography and determination of the NH2-terminal amino acids. The abnormal fibrinogen formed a solid gel solely by the release of fibrinopeptide B upon incubation with thrombin. We provisionally designate this abnormal fibrinogen as "Fibrinogen Kawaguchi", although possible identity with other abnormal fibrinogens is not excluded.
Adult↗
Glucocorticoid-lens protein adducts in experimentally induced steroid cataracts.
The injection of glucocorticoids into the vitreous chamber of the rabbit eye results in the development of posterior subcapsular opacities. These lesions appear to be similar in morphology to human steroid-induced cataracts. Electron microscopic analysis revealed fiber cell separation, vacuolization, and changes within the matrix of the crystallins. Opacification could only be produced by glucocorticoids possessing a reactive C-20,21 hydroxylcarbonyl function, supporting the hypothesis that glucocorticoid addition products are involved in the induction of these lesions. The occurrence of glucocorticoid-lens proteins adducts was confirmed by tritium incorporation and by radioimmunoassay of protein hydrolysates obtained from these lenses.
17-alpha-Hydroxyprogesterone↗
Nonenzymatic modification of lens crystallins by prednisolone induces sulfhydryl oxidation and aggregate formation: in vitro and in vivo studies.
Steroid-induced cataracts occur as a consequence of prolonged, therapeutic levels of glucocorticoids. Previous studies have shown that these lens opacities are associated with the occurrence of covalent glucocorticoid-lens protein adducts. In vitro, the glucocorticoid prednisolone nonenzymatically modifies the lysine residues of lens crystallins. This modification increases the reactivity of protein thiols and leads to the formation of high-molecular-weight, disulfide-linked aggregates. Prednisolone-induced aggregates result in an opalescence in the crystallins solution which is reversed by the addition of dithiothreitol. The acetylation of lens proteins prior to incubation inhibits both the incorporation of prednisolone and the development of opalescence. Gel filtration chromatography of the prednisolone lens protein incubations shows that the majority of the protein-incorporated prednisolone is associated with the disulfide-linked complexes. Similar analysis of proteins obtained from a human steroid-induced cataract demonstrates that prednisolone adducts which form in vivo are also present in reducible, high-molecular-weight complexes. These results implicate the nonenzymatic modification of lens crystallins in the cataractogenic effect of glucocorticoids and suggest possible pharmacological strategies in preventing this toxic manifestation of steroid therapy.
Acetylation↗
[Immunocytologic identification of blood group substances in blood and bone marrow smears--its usefulness in bone marrow transplantation and leukemia].
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ABO Blood-Group System↗
[Quantitative analysis of rheumatoid factor with latex agglutination].
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Arthritis, Rheumatoid↗
Cadmium-induced stimulation of lipogenesis from glucose in rat adipocytes.
Exposure of adipocytes of rats to CdCl2 caused acceleration of [3-3H]glucose incorporation into lipid maximally at 500 microM in Krebs-Ringer bicarbonate buffer, pH 7.4, containing 0.2% albumin. T.l.c. of the lipids extracted from adipocytes showed that Cd2+ increased labelling of di- and tri-[14C]acylglycerols predominantly. With increasing concentrations of glucose the apparent Km value was not affected by Cd2+, but the V value was increased, similarly to the effect of insulin. In the presence of insulin, Cd2+ (5 microM) exerted a consistent additive effect with a stimulatory effect of insulin on lipogenesis at all concentrations of insulin tested (5-50 mu units/ml). The stimulation was observed at a high concentration of glucose, suggesting that Cd2+ accelerated intracellular metabolism of glucose, mimicking insulin. However, although Zn2+ and Mn2+ stimulated the transport at a rate similar to that observed with insulin (200 mu units/ml), Cd2+ had no stimulating effect on the membrane transport of 3-O-methylglucose. The biological potency of Cd2+ and the insulin-like effects of Zn2+, both of which metals belong to the same group in the Periodic Table, are similar towards glucose metabolism, but quite different towards glucose transport.
3-O-Methylglucose↗
Species difference in sensitivity to the diabetogenic action of triphenyltin hydroxide.
The sensitivity to the diabetogenic action of triphenyltin hydroxide (TPTOH) was investigated in 5 species of experimental animals. A single oral administration of TPTOH produced marked hyperglycemia and triglyceridemia in rabbits and hamsters, but no evidence of diabetes was found in mice, rats and guinea-pigs. No morphological abnormality was observed in islet tissue from TPTOH-treated hamsters.
Animals↗
Nonenzymatic addition of glucocorticoids to lens proteins in steroid-induced cataracts.
A frequent manifestation of long-term glucocorticoid administration is the occurrence of posterior subcapsular cataracts. The molecular basis for this effect has not yet been elucidated. The addition of prednisolone to the rat lens in culture results in a time- and concentration-dependent lens opacification that correlates with the formation of covalent prednisolone-lens protein adducts. Prednisolone adduct formation was analyzed by [3H]prednisolone incorporation and by immunoprecipitation with antiserum specific for proteins modified by the nonenzymatic addition of prednisolone. In the rat lens, these adducts were localized in both the water-soluble and urea-soluble lens protein fractions. Gel electrophoresis and fluorography revealed that the most extensively modified proteins were two crystallins subunits. Lens proteins from 33 normal and cataractous human lenses were fractionated and analyzed for the presence of prednisolone-protein adducts by competitive radioimmunoassay. Adducts were detected only in those samples derived from glucocorticoid-induced cataractous lenses. We conclude that elevated glucocorticoid levels lead to the formation of glucocorticoid-lens protein adducts both in vitro and in vivo. Lens protein modification by glucocorticoids may lead to sufficient biochemical or structural alterations so as to result in cataract formation. The ability of glucocorticoids to form adducts with proteins in vivo also may play a role in some of the other toxic manifestations of long-term glucocorticoid therapy.
Animals↗
Triphenyltin fluoride in vitro inhibition of rabbit platelet collagen-induced aggregation and ATP secretion and blockade of arachidonic acid mobilization from membrane phospholipids.
Recent studies have demonstrated that triphenyltin fluoride (TPTF) inhibits collagen-induced aggregation and ATP secretion of rabbit platelets in vivo [S. Manabe and O. Wada, J. Toxic. Sci. 6, 236 (1981)]. The aim of the present investigation was to test the effects in vitro of TPTF on platelet aggregation and to elucidate the mechanism of the inhibitory action by studying the release and metabolism of arachidonic acid and the cyclic AMP contents of rabbit platelets treated in vitro with TPTF. Although no inhibitory effect of TPTF was found on sodium arachidonate-induced platelet aggregation and ATP secretion, TPTF inhibited both reactions induced by collagen. Triphenylarsine and triphenylantimony did not inhibit, even at a concentration of 10(-3) M. The anti-aggregating concentration (IC50) of TPTF was 6.0 x 10(-6) M against collagen. TPTF had no inhibitory effect on the conversion of exogenous arachidonic acid to malondialdehyde (MDA) by platelets, while the collagen-induced production of arachidonate metabolites [MDA, 12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and thromboxane B2] was remarkably inhibited by TPTF. Furthermore, TPTF apparently inhibited the collagen-induced release of arachidonic acid from platelets, although the formation of phosphatidic acid was not inhibited. Total cyclic AMP content after TPTF exposure was not changed significantly. These results indicate that TPTF inhibited the collagen-induced arachidonic acid release from platelet phospholipids, presumably by acting on phospholipase A2. Furthermore, it seems unlikely that the inhibition of arachidonic acid release by TPTF can be explained by the level of cyclic AMP in platelets.
Adenosine Triphosphate↗