Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of Triton WR-1339 and phenobarbital on ethinyl estradiol bile secretory failure were examined to determine the mechanism responsible for decreased bile salt excretion. When administered to ethinyl estradiol-treated rats, Triton WR-1339 restored bile salt independent bile flow and maximum taurocholate transport, whereas phenobarbital corrected bile flow only. Ethinyl estradiol decreased the activities of Na(+)-K(+)-ATPase, 5'-nucleotidase, while increasing the activities of Mg(++)-ATPase and alkaline phosphatase. In contrast to these heterogeneous changes in surface membrane enzyme activities, the number and affinity of [(14)C]cholic acid carriers were not altered. When administered in vivo or added directly to surface membrane fractions Triton WR-1339 restored the activities of Na(+)-K(+)-ATPase and Mg(++)-ATPase of rats treated with ethinyl estradiol through a process that did not require protein synthesis (unaffected by cycloheximide). Phenobarbital also restored the activity of Na(+)-K(+)-ATPase to control levels, but, unlike Triton WR-1339 it did not correct the defect responsible for reduced bile salt secretion. Ethinyl estradiol increased the concentration of cholesterol esters in surface membrane fractions. When administered to ethinyl estradiol-treated rats, Triton WR-1339 restored cholesterol ester concentrations to normal, whereas phenobarbital did not. These combined data suggest that decreased or altered bile salt carriers or reduced sodium driving forces resulting from impaired activity of Na(+)-K(+)-ATPase are not responsible for decreased bile salt excretion in ethinyl estradiol-treated rats. It is proposed that the diverse changes in surface membrane function, which are associated with ethinyl estradiol bile secretory failure, may be the result of a generalized alteration in membrane lipid structure.
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PMID:Reversal of ethinyl estradiol-induced bile secretory failure with Triton WR-1339. 624 35

The outer 150-micrometers layer of the renal cortex of the rat consists mainly of proximal tubules (PT). In this layer Na-K-ATPase (mumol Pi . mg protein-1 . h-1) increases from 3.45 +/- 0.19 (SE) in 10-day-old rats (R10) to 5.90 +/- 0.28 in 20-day-old rats (R20) to 9.52 +/- 0.42 in 40-day-old rats (R40). Betamethasone in pharmacologic doses increases Na-K-ATPase in R10, R20, and R40 to 11.5 +/- 1.19, 13.4 +/- 0.64, and 13.3 +/- 0.60, respectively. Estrogen in pharmacologic doses increases Na-K-ATPase to 9.1 +/- 0.46 in R20 and decreases Na-K-ATPase to 7.6 +/- 0.39 in R40. Aldosterone in a dose of 10 micrograms/100 g BW increases Na-K-ATPase to 8.7 +/- 0.26 in R20; in a dose of 40 micrograms/100 g BW it increases Na-K-ATPase to 6.9 +/- 0.35 in R10. However, aldosterone in a dose of 80 micrograms/100 g BW is needed to cause an increase in R40 to 13.4 +/- 0.37. Treatment with canrenone from the 10th to the 20th day increases Na-K-ATPase. It is concluded that the immature PT cells are particularly sensitive to hormone induction of Na-K-ATPase and that the sensitivity is maximal during fairly late stages of cellular differentiation. Moreover, the inductive effect is probably mediated via glucocorticoid receptors.
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PMID:Hormonal induction of Na-K-ATPase in developing proximal tubular cells. 627 4

Structural and functional changes in the surface membranes of hepatocytes play a pivotal role in the induction and reversion of some forms of drug-induced cholestasis. To elucidate the mechanism by which S-adenosyl-L-methionine (SAMe) leads to a partial reversion of bile flow impairment caused by ethinyl estradiol (EE), female Sprague-Dawley rats were given oral doses of EE (5 mg per kg per day, for 3 days) with and without simultaneous administration of SAMe (25 mg per kg, 3 times per day, for 3 days). Na+,K+-ATPase activity and membrane microviscosity as measured by fluorescent polarization were assayed in isolated liver plasma membranes (LPMs). SAMe administration to normal and EE-treated rats resulted in a marked increase in Na+,K+-ATPase activity and LPM fluidity. EE alone did not cause any change in the physicochemical properties of the LPMs. Hepatic Mg2+-ATPase and gamma-glutamyl transpeptidase activities were not affected by SAMe alone but increased when SAMe was given together with EE. These data indicate that the interaction of in vivo administered SAMe with hepatocyte plasmalemma and its effect on lipid fluidity and enzymes of the LPMs showed a high specificity and an inverse relationship between Na+,K+-ATPase activity and fluorescence polarization values. Furthermore, modulation of hepatic Na+,K+-ATPase was associated with SAMe-induced protection against bile flow impairment due to EE; however, it was not the causative factor for EE-induced cholestasis under the experimental conditions. These findings suggest that changes in surface membrane structure and function might account in part for the reversal by SAMe of EE-induced impairment of bile secretory function.
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PMID:Modulation by S-adenosyl-L-methionine of hepatic Na+,K+-ATPase, membrane fluidity, and bile flow in rats with ethinyl estradiol-induced cholestasis. 629 6

Taurocholic uptake in ethinyl estradiol cholestatic rats is significantly lower than in untreated rats. In the days following treatment withdrawal there is only a slow increase in uptake, which is still statistically lower than normal at the 11th day. Taurocholic acid uptake behaves in a different way from biliary flow and the amount of excreted bile acids. The diversity could be attributed to a different behaviour of bile acid carriers at the sinusoidal and biliary membranes in the hepatocyte or to a normalisation of bile acid carriers and Na+,K+,-ATPase activity at different times.
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PMID:Hepatocyte taurocholic acid uptake in the regression of ethinyl estradiol cholestasis. Preliminary results. 671 17

Although oral contraceptives (OCs) are yet to be legalized in Japan, it is estimated that at least 500,000 women were on pills in 1975. Intrahepatic cholestasis has been associated with OC in the Western countries, but only a few cases have been reported in Japan. A case of pill-related intrahepatic cholestasis in a 25-year old housewife will be presented in terms of clinical/pathological findings, changes in plasma and bile acid levels, and the effect of phenobarbital on bile stagnation. The patient had been taking 1 pill (Anovlar)/day, 25 days a month, for 5 months, and had experienced exhaustion, nausea, and constipation after 3 months of use; body itch and jaundice symptoms after 4 months. Cholangiography showed neither enlargement of the bile duct nor obstruction of the bile duct outside the liver. The condition was diagnosed as pill-related intrahepatic cholestasis. Total bilirubin was considerably raised; serum transaminase was moderately raised. Electromicroscopy showed the enlargement of bile canaliculi, which had electron dense bile content. Hepatic cellular peroxisome significantly increased. Plasma bile acid level, which was slightly raised initially, came down to the normal range when total bilirubin was back to normal with daily administration of phenobarbital 2 mg/kg. Studies which included experiments with rats as well as clinical-pathological results mentioned above suggested that bile stagnation was caused by ethinyl estradiol. By lowering bile canaliculi Na-K ATPase activity, ethinyl estradiol decreased bile acid independent of bile flow. Phenobarbital was effective for cholestasis by increasing bile canaliculi Na-K ATPase activity.
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PMID:[Intrahepatic cholestasis caused by oral contraceptives]. 714 55

Treatment with ethinyl estradiol is known to impair bile formation, bile acid transport and Na,K-ATPase activity, to alter receptor-mediated endocytosis and transcytosis of IgA and asialoorosomucoid and to affect membrane lipid composition and fluidity. Because appropriate sorting and trafficking of asialoorosomucoid requires adequate acidification of endocytic vesicles by a lipid-sensitive electrogenic proton pump, we examined the effects of 5 days of treatment with ethinyl estradiol (5 mg/kg body wt, subcutaneously) on acidification of early endosomes prepared from male rat livers. Littermate control animals received equal volumes of the solvent propylene glycol. Pretreatment with ethinyl estradiol reduced ATP-dependent initial rates of endosome acidification by 11% to 25% when measured in potassium medium containing 0 to 140 mmol/L chloride; these differences were significant at four of six chloride concentrations tested. The proton pumps of ethinyl estradiol and propylene glycol endosomes exhibited similar Michaelis-Menten constants for MgATP (Michaelis-Menten constant of 63 and 66 mumol/L in the absence of chloride and 101 and 126 mumol/L in the presence of chloride, respectively). Acidification of ethinyl estradiol and propylene glycol endosomes changed in the same manner when various cations or anions were substituted for potassium gluconate, although the effects of ethinyl estradiol were less marked in the absence of K+. Kinetics of inhibition for ethinyl estradiol and propylene glycol endosomes were similar for the proton pump inhibitors N-ethylmaleimide (50% inhibitory concentrations of 13.5 and 18.1 mumol/L), dicyclohexylcarbodiimide (50% inhibitory concentrations of 206 and 216 mumol/L) and bafilomycin A (50% inhibitory concentrations of 11 and 6 nmol/L). Although initial rates of acidification were slower in ethinyl estradiol endosomes, ATP-dependent steady-state vesicle interior pH was the same as that of propylene glycol endosomes over a range of chloride concentrations; this appeared to be due mainly to a trend toward decreased proton leak rates in ethinyl estradiol endosomes. Overall, ethinyl estradiol treatment modestly decreased initial rates of acidification and vesicle proton leakage, perhaps because of changes in endosome lipid composition; differences in the number, density or activation state of proton pumps; or differences in endosome geometry. Because the decrease in acidification rates was small, the effects of estrogen on the efficiency of uncoupling of endocytosed ligands such as asialoorosomucoid from their receptors in early endosomes; thus the rates of sorting and distribution of ligands remain unclear.
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PMID:Ethinyl estradiol decreases acidification of rat liver endocytic vesicles. 835 2

The mechanisms involved in ethinyl estradiol-induced cholestasis are controversial. Basal bile flow was reduced by ethinyl estradiol administration, with a half time (t1/2) of 12.5 +/- 0.6 h. In contrast, initial taurocholate uptake was not significantly reduced until 3 days to 59% of control and to 13 and 10% of control at 5 and 7 days, respectively. The t1/2 was 4.3 +/- 0.1 days. These physiological changes were correlated with measurement of protein mass and steady-state mRNA for Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase), Na(+)-dependent taurocholate transporter, organic anion transporters, and membrane lipid fluidity. Ethinyl estradiol significantly decreased Na(+)-K(+)-ATPase activity and membrane fluidity. However, neither Na(+)-K(+)-ATPase alpha-subunit nor beta-subunit mass was altered by ethinyl estradiol administration. In contrast, protein content of the Na(+)-dependent taurocholate transporter was significantly reduced to 21% of control (P < 0.001) at 5 days. The Na(+)-dependent taurocholate transporter was identified in sinusoidal membrane fractions as a doublet with a molecular size estimated to be 51 and 56 kDa. Although both bands were reduced with ethinyl estradiol treatment, the 56-kDa band was decreased more rapidly and to a greater extent than the 51-kDa band. The estimated t1/2 of 4.8 +/- 0.6 days for the doublet was similar to that for Na(+)-dependent taurocholate uptake. The organic anion transporter protein mass was similarly reduced with time of ethinyl estradiol administration to 21% of control (P < 0.01) at 5 days. Ethinyl estradiol also rapidly decreased the steady-state mRNA levels of Na(+)-dependent and organic anion transporters to approximately 50% and 15% of control at 5 days, respectively. These studies indicate early generalized abnormalities of the sinusoidal membrane lipid fluidity, Na(+)-K(+)-ATPase activity, and bile acid transport protein content.
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PMID:Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters. 899 49

Synapse loss, deposits of amyloid beta-peptide (Abeta), impaired energy metabolism, and cognitive deficits are defining features of Alzheimer's disease (AD). Estrogen replacement therapy reduces the risk of developing AD in postmenopausal women. Because synapses are likely sites for initiation of neurodegenerative cascades in AD, we tested the hypothesis that estrogens act directly on synapses to suppress oxidative impairment of membrane transport systems. Exposure of rat cortical synaptosomes to Abeta25-35 (Abeta) and FeSO4 induced membrane lipid peroxidation and impaired the function of the plasma membrane Na+/K+-ATPase, glutamate transporter, and glucose transporter. Pretreatment of synaptosomes with 17beta-estradiol or estriol largely prevented impairment of Na+/K+-ATPase activity, glutamate transport, and glucose transport; other steroids were relatively ineffective. 17Beta-estradiol suppressed membrane lipid peroxidation induced by Abeta and FeSO4, but did not prevent impairment of membrane transport systems by 4-hydroxynonenal (a toxic lipid peroxidation product), suggesting that an antioxidant property of 17beta-estradiol was responsible for its protective effects. By suppressing membrane lipid peroxidation in synaptic membranes, estrogens may prevent impairment of transport systems that maintain ion homeostasis and energy metabolism, and thereby forestall excitotoxic synaptic degeneration and neuronal loss in disorders such as AD and ischemic stroke.
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PMID:17Beta-estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid beta-peptide and iron. 940 14

Estrogen has been shown to help maintain the elevated expression of the high ATPase myosin isoform, V1, present in the hearts of young rats (< 70 days of age). Because hearts of this age are still undergoing significant maturation, the current study sought to determine if estrogen similarly regulates myosin isoenzyme expression in the mature adult heart. To make this determination, ten month old retired female Sprague-Dawley rats were made estrogen-deficient by ovariectomy (OVAR, n = 8). Sham-operated (CONTR, n = 8) animals served as controls. Nine weeks later, the animals were sacrificed and left ventricular tissue collected. Crude myofibrills were isolated from these samples and electrophoretically separated into the three isoenzymatic forms of cardiac myosin (V1, V2, and V3). OVAR animals were larger than the CONTR group (p < 0.05), but heart weight/body weight ratios were not different between groups. Distribution of myosin among its three isoenzymes was similar between groups (CONTR: V1, 80%, V2, 14%; V3, 6%; OVAR: V1, 77%, V2, 16%, V3, 7%). These data demonstrate that myosin isoenzyme distribution in the adult heart is unaltered by ovariectomy, suggesting that estrogen loses its ability to regulate expression of this protein in the mature heart.
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PMID:Ovariectomy fails to modify the cardiac myosin isoenzyme profile of adult rats. 954 90

Estrogen and progesterone, while regulating uterine functions, also regulate the number of caveolae and the level of caveolin. Large numbers of caveolae, as well as elevated expression of caveolin-1 and caveolin-2 isoforms in the myometrium of ovariectomised (OVX) rats were detected. 17beta-estradiol (E2) has a downregulating effect: the treatment of OVX rats with E2 (5 microg/animal) reduced the formation of caveolae by approx. 90%. Western blots clearly demonstrated the reduction of membrane caveolin-1 and -2 content. Progesterone treatment (2.5 mg/animal) alone did not cause any substantial change, but prevented the effect of estrogen. Control experiments showed that the quantity of Na+/K+-ATPase, a plasma membrane protein excluded from caveolae, was not downregulated by E2. The administration of the pure estrogen receptor (ERalpha) antagonist ICI 182,780 (1 mg/animal) not only compensated for the inhibitory effect of E2, but further increased the level of caveolin-1 in the myometrium of OVX rats and facilitated the formation of caveolae by approximately 70%. In contrast, the partial antagonist tamoxifen (1 mg/animal) mimicked the effect of estrogen. The amount of caveolin also changed during pregnancy. During the first half of pregnancy the expression of caveolin was suppressed, but it gradually increased until delivery. Our results indicate that the formation and number of caveolae are influenced by the physiological state of the uterus in a hormone dependent manner.
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PMID:Estrogen downregulates the number of caveolae and the level of caveolin in uterine smooth muscle. 1148 2


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