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 transverse distribution of enzyme proteins and phospholipids within microsomal membranes was studied by analyzing membrane composition after treatment with proteases and phospholipases. Upon trypsin treatment of closed microsomal vesicles, NADH- and NADPH-cytochrome c reductases as well as cytochrome b5 were solubilized or inactivated, while cytochrome P-450 was partially inactivated. When microsomes were exposed to a concentration of deoxycholate which makes them permeable to macromolecules but does not disrupt the membrane, the detergent alone was sufficient to release four enzymes: nucleoside diphosphatase, esterase, beta-glucuronidase, and a portion of the DT-diaphorase. Introduction of trypsin into the vesicle lumen inactivated glucose-6-phosphatase completely and cytochrome P-450 partially. The rest of this cytochrome, ATPase, AMPase, UDP-glucuronyltransferase, and the remaining 50% of DT-diaphorase activity were not affected by proteolysis from either side of the membrane. Phospholipase A treatment of intact microsomes in the presence of albumin hydrolyzed all of the phosphatidylethanolamine, phosphatidylserine, and 55% of the phosphatidylcholine. From this observation, it was concluded that these lipids are localized in the outer half of the bilayer of the microsomal membrane; Phosphatidylinositol, 45% of the phosphatidylcholine, and sphingomyelin are tentatively assigned to the inner half of this bilayer. It appears that the various enzyme proteins and phospholipids of the microsomal membrane display an asymmetric distribution in the transverse plane.
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PMID:Enzyme and phospholipid asymmetry in liver microsomal membranes. 19 Feb 41

We have previously reported that a component of ADP-evoked Ca2+ entry in human platelets appears to be promoted following the release of Ca2+ from intracellular stores. Other agonists may employ a similar mechanism. Here we have further investigated the relationship between the state of filling of the Ca2+ stores and plasma membrane Ca2+ permeability in Fura-2-loaded human platelets. Ca2+ influx was promoted following store depletion by inhibitors of the endoplasmic reticulum Ca(2+)-ATPase, thapsigargin (TG) and 2,5-di-(t-butyl)-1,4-benzohydroquinone (tBuBHQ). Divalent cation entry was confirmed by quenching of Fura-2 fluorescence with externally added Mn2+. It has been suggested that cytochrome P-450 may couple Ca2+ store depletion to an increased plasma membrane Ca2+ permeability. In apparent agreement with this, Mn2+ influx promoted by TG and tBuBHQ, or by preincubation of cells in Ca(2+)-free medium, was inhibited by the imidazole antimycotics, econazole and miconazole, which inhibit cytochrome P-450 activity. Agonist-evoked Mn2+ influx was only partially inhibited by these compounds at the same concentration (3 microM). Econazole (3 microM) reduced the Mn2+ quench evoked by ADP by 38% of the control value and that evoked by vasopressin, platelet activating factor (PAF) and thrombin no more than 15% of control, 20 s after agonist addition. Stopped-flow fluorimetry indicated that econazole had no detectable effect on the early time course of agonist-evoked Mn2+ entry or rises in [Ca2+]i. These data confirm the existence of a Ca2+ entry pathway in human platelets which is activated by depletion of the intracellular Ca2+ stores. Further, the results support the suggestion that cytochrome P-450 may participate in such a pathway. However, any physiological role for the cytochrome or its products in agonist-evoked events appears to be in the long-term maintenance or restoration of store Ca2+ content, rather than in promoting Ca2+ influx in the initial stages of platelet Ca2+ signal generation.
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PMID:Calcium influx evoked by Ca2+ store depletion in human platelets is more susceptible to cytochrome P-450 inhibitors than receptor-mediated calcium entry. 133 9

The effect of lead on hepatic mitochondria and microsomes of chick embryo was studied with special attention to the role of lipid peroxidation in the manifestation of lead toxicity. Mitochondrial enzymes such as succinate dehydrogenase, cytochrome C oxidase and ATPase were found to decrease in a dose dependent manner upon lead administration. Further, mitochondrial cytochromes, microsomal cytochrome P-450 and heme levels were reduced considerably with concomitant increase of mitochondrial and microsomal lipid peroxides. In the present investigation an attempt has been made to correlate the lead induced lipid peroxidation, the loss of mitochondrial and microsomal hemoproteins and the inhibition of mitochondrial enzymes in chick embryo.
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PMID:Effect of lead on lipid peroxidation of the hepatic subcellular organelles of developing chick embryos. 141 14

In addition to cyclooxygenase and lipoxygenase, arachidonic acid (AA) is metabolized by the cytochrome P-450 monooxygenase system. The kidney is one of the major extrahepatic tissues that display cytochrome P-450 enzyme activities, in particular the cortex, specifically the proximal tubule demonstrate the highest concentration. AA is metabolized by the renal cytochrome P-450 epoxygenase and omega/omega 1 hydroxylases to epoxyeicosatrienoic acids and omega/omega-1 alcohols (20- and 19-mono-hydroxyeicosatetraenoic acids), respectively. These metabolites possess a broad spectrum of biological and renal effects which include: vasodilation, vasoconstriction, inhibition and stimulation of Na(+)-K(+)-ATPase, inhibition of ion transport mechanisms, natriuresis, inhibition of renin release and stimulation of cell growth. These metabolites are endogenous constituents of the kidney and are present in urine with increasing concentration under pathological conditions such as pregnancy-induced hypertension. The cytochrome P-450-dependent metabolism of AA is specifically localized to the proximal tubule and exhibits developmental changes, i.e., renal production of metabolites is very low in the fetus, newborn and up to 3 weeks of age, after which a remarkable increase in enzyme activities is observed. These characteristics call attention to the importance of this enzyme system in producing cellular mediators for regulating renal function in normal and diseased states.
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PMID:The renal cytochrome P-450 arachidonic acid system. 145 35

Epoxygenase and omega- and omega-1-hydroxylases are the major cytochrome P-450-arachidonate (P-450-AA) metabolizing enzymes in renal tissues. We measured P-450-AA metabolism in single nephron segments and determined the tubular localization of this activity in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Formation of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of AA omega-hydroxylase was specifically localized in the entire proximal tubules (S1, S2, and S3 segments), whereas formation of 19-HETE, the product of omega-1-hydroxylase and epoxyeicosatrienoic acids (EETs), products of AA epoxygenase, was demonstrable throughout the tubule. Although distribution patterns were similar in SHR and WKY, formation of 19- and 20-HETE in the proximal tubules was higher in SHR, whereas the formation of EETs was not different between the two strains. In the proximal tubules, angiotensin II (ANG II) significantly stimulated epoxygenase activity (EETs formation), whereas parathyroid hormone (PTH) and epidermal growth factor (EGF) had no effect on epoxygenase but significantly stimulated omega-hydroxylase activity (20-HETE formation). Because P-450-AA metabolites have a wide and contrasting spectrum of biological and renal effects, from vasodilation to vasoconstriction and from inhibition to stimulation of Na(+)-K(+)-adenosinetriphosphatase, their localization to the specific nephron segments and differential stimulation of their formation by ANG II, PTH, and EGF may contribute not only to renal hemodynamics and blood pressure regulation but also to the regulation of renal sodium and water balance.
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PMID:Renal cytochrome P-450-arachidonic acid metabolism: localization and hormonal regulation in SHR. 156 72

We recently demonstrated that renal synthesis of cytochrome P-450-dependent arachidonic acid (AA) metabolites is increased in spontaneously hypertensive rats (SHR) during the rapid elevation of blood pressure. In this study, the chemical identity of these metabolites is described, and the structural analysis together with differential susceptibility to antibodies suggested that they are derived from at least two different cytochrome P-450 isozymes: 1) the epoxygenase that metabolizes AA mainly to 11,12-epoxyeicosatrienoic acid (EET), which is further hydrolyzed to 11,12-dihydroxyeicosatrienoic acid (DHT) and 2) omega/omega-1 hydroxylase(s) that generate the 20-hydroxyeicosatetraenoic acid (HETE) and 19-HETE, respectively. Their production and release from the isolated kidney was activated by arginine vasopressin and inhibited by cytochrome P-450 enzyme inhibitors. The formation of these metabolites in SHR or WKY cortical microsomes was age dependent. The production rates of EET, DHT, and 19-HETE increased from fetal to 9 wk of age by 3-, 6- and 4-fold, respectively, whereas that of 20-HETE increased by 27-fold. The omega/omega-1 hydroxylase activities were significantly higher in SHR, whereas epoxygenase activity (sum of EET and DHT production) demonstrated no differences between the two strains at any age group tested, although the amount of EET vs. DHT in a given age was significantly different. Since these metabolites have a wide and contrasting spectrum of biological and renal effects (vasodilation and vasoconstriction, inhibition and stimulation of Na(+)-K(+)-ATPase), their relative production rates at a given age may influence not only renal hemodynamics and salt and water balance but also pro- and antihypertensive mechanisms in SHR.
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PMID:Age-related changes in renal cytochrome P-450 arachidonic acid metabolism in spontaneously hypertensive rats. 173

Two biologically active cytochrome P-450 arachidonate metabolites previously were characterized: 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(R)-HETE) and 12(R)-hydroxy-5,8,14-eicosatrienoic acid (12(R)-DH-HETE), which are endogenously formed in the corneal epithelium. The functional activity of these novel metabolites mimics changes observed in hypoxic corneas. Therefore, the effect of hypoxic stress was examined on metabolite formation in rabbits fitted with polymethylmethacrylate contact lenses. Although applied lenses fit tightly to the rabbit cornea, mechanical irritation also may contribute to the ocular response. Contact lens-induced hypoxic stress stimulated endogenous formation of both 12(R)-HETE (a sodium, potassium adenosine triphosphatase inhibitor) and 12(R)-DH-HETE (a vasodilatory, chemotactic, and angiogenic factor) in a time-dependent manner. After 4 hr of contact lens wear, a 21-fold increase in endogenous 12(R)-HETE formation concomitant with an increase in corneal thickness was observed. After prolonged contact lens wear (144 hr), a 23-fold increase in endogenous 12(R)-DH-HETE formation was found, corresponding with the appearance of a marked conjunctival inflammation characterized by corneal neovascularization. The increased formation of these compounds was associated with time-dependent changes in corneal endothelial morphology. The ability of 12(R)-HETE and 12(R)-DH-HETE to mediate the clinical signs of corneal hypoxia suggest these metabolites may be potential mediators of contact lens complications that followed conditions of hypoxic stress and possibly mechanical irritation in this model.
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PMID:Induction of corneal epithelial cytochrome P-450 arachidonate metabolism by contact lens wear. 174 Mar 58

Interactions with the hepatic cytochrome P-450 microsomal enzyme system, as evidenced by statistically significant changes in pharmacokinetic parameters, have been described with some H2-receptor antagonists. Omeprazole is the first of a new class of antisecretory agents inhibiting gastric secretion by blocking hydrogen potassium ATPase. Omeprazole contains a benzimidazole moiety and thus has the potential to interact with the cytochrome P-450 enzyme group. In vitro, in vivo and human clinical studies have assessed whether such an interaction occurs, and the potential clinical consequences, in patients receiving omeprazole therapy. In vitro studies have demonstrated that omeprazole influences O-deethylation and N-demethylation in liver microsomes and the clearance and elimination half-life of antipyrine in isolated perfused liver preparations. Overall, the studies reviewed suggest that omeprazole has a differential affinity toward specific cytochrome P-450 isozymes. In vivo animal studies have demonstrated that omeprazole prolongs pentobarbital sleep times and half-life and decreases [14C]-aminopyrine elimination. Human clinical studies have not demonstrated the "all or none" effect of omeprazole on cytochrome P-450-mediated drug interactions, as is seen with cimetidine. These studies confirm in vitro findings that omeprazole is a differential inhibitor of drug metabolism: interactions have been demonstrated with the model drugs aminopyrine and antipyrine, and the therapeutic drugs diazepam, phenytoin, and warfarin but not with theophylline or propranolol. Although caution should be exercised when initiating omeprazole therapy in patients taking concomitant diazepam, warfarin, and phenytoin, clinically significant drug interactions appear unlikely.
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PMID:Clinical implications of drug interactions with the cytochrome P-450 enzyme system associated with omeprazole. 174 33

We studied the effects of K+ on cytochrome P-450-dependent arachidonic acid (P450-AA) metabolism by cells isolated from the rabbit medullary thick ascending limb of Henle's loop (MTAL) by varying K+ from 0 to 7.5 mM in the incubating medium because of the known effects of K+ on AA metabolism. Rabbit MTAL cells convert AA to metabolites that segregate into two peaks (P1 and P2) on reverse-phase high-performance liquid chromatography; P1 contains vasodilator material and P2 an inhibitor(s) of Na(+)-K(+)-ATPase activity. Formation of P450-AA metabolites by MTAL was enhanced by reducing external K+ (P less than 0.01) and was not affected by changes in external Cl- but was dependent on the presence of intact MTAL cells, suggesting that P450-AA metabolism was related to altering ion fluxes and/or cell volume changes. The effects of altered external K+ on MTAL P450-AA metabolism could be nullified by increasing K+ intake before killing the rabbits. Evidence for the absence of a direct effect of zero K+ on Na(+)-K(+)-ATPase was provided by the demonstration that ouabain failed to affect AA metabolism in MTAL cells. We conclude that P450-AA metabolism by MTAL cells can be influenced either directly by altering external K+ in the incubate or indirectly by changing dietary K+ before killing the rabbits. Furthermore, MTAL P450-AA metabolism was independent of changes in external Cl- and Na(+)-K(+)-ATPase activity.
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PMID:K+ alters cytochrome P-450-dependent arachidonate metabolism by rabbit renomedullary cells. 210 31

In the presence of NADPH cytochrome P-450-dependent monooxygenases oxidize arachidonic acid giving rise to four epoxyeicosatrienoic acids (EETs) which are hydrolyzed enzymatically to dihydroxyeicosatrienoic acids (DHETs). EETs generate vasodilators. Allylic oxidation forms hydroxyeicosatetraenoic acids, of which 12(R)HETE is an inhibitor of Na(+)-K(+)-ATPase and renin release. Finally, omega and omega-1 hydroxylation of arachidonic acid generates 20- and 19-HETEs which are involved in the development of hypertension in SHR rats.
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PMID:Cytochrome P-450 metabolites of arachidonic acid: implications for blood pressure regulation. 212 86


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