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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adrenal cortical mitochondria contain a mixed function oxidase capable of converting cholesterol to pregnenolone; this enzyme requires NADPH, oxygen and cholesterol. This cholesterol side chain cleavage enzyme system contains a Flavoprotein, an iron sulphur protein and a specific cytochrome P450 termed cytochrome P450scc. ACTH stimulates the adrenal cortex by activating adenyl cyclase producing an elevated intracellular concentration of cAMP. This in turn increases the activity of a cytosolic cAMP dependent protein kinase. Adrenal cortical cytosol contains a cholesterol ester hydrolase which is activated by ATP and a protein kinase. This enzyme may be deactivated by a phosphoprotein phosphatase. The adrenal cortex contains lipid droplets that are rich in esterified cholesterol. Cholesterol ester hydrolase can release free cholesterol from the lipid droplets. The free cholesterol released may be used to supplement the mitochondrial cholesterol as a pregnenolone precursor. Steroid hormone production by the adrenal cortex exhibits a diurnal rhythm and correlates with the activity of the cytosolic cholesterol ester hydrolase. The acute steroidogenic response to ACTH may be in part attributed to the availability of free cholesterol to the mitochondrial cholesterol side chain cleavage enzyme complex. The intracellular movement of free cholesterol from lipid droplets to mitochondrial inner membranes may be impeded by protein synthesis inhibitors such as cycloheximide. The precise mechanism of this block in steroidogenesis remains to be elucidated. Various drugs and oestrogenic hormones suppress the plasma and adrenal cholesterol concentrations. If adrenal cells are deficient in cholesterol, these cells exhibit a diminished response to ACTH. The response to this hormone can be corrected by supplying cholesterol via exogenous plasma lipoproteins. The route that free cholesterol follows within the adrenal cortical cell and the physiological factors influencing free cholesterol movement in such cells are important issues to be explored in future.
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PMID:Cholesterol metabolism in the adrenal cortex. 631 Feb 52

We investigated the inhibitory effects of intracellular cyclic adenosine monophosphate (cAMP) levels in regulating class 3 aldehyde dehydrogenase (aldh3) gene expression using cultures of primary rat hepatocytes and transient transfection experiments with HepG2 cells. In addition to regulation by an Ah receptor-dependent mechanism, expression of many members of the Ah gene battery have been shown to be negatively regulated. As was seen for the cytochrome P450 (cyp1A1) gene, aldh3 is transcriptionally inducible by polycyclic aromatic hydrocarbons (PAH), and this induction involving function of the arylhydrocarbon (Ah) receptor is inhibited by the protein kinase C (PKC) inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine di-HCl (H7) and staurosporine. However, PAH induction of ALDH-3 activity, protein, and mRNA was potentiated 2-4-fold by addition of the protein kinase A (PKA) inhibitors, N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide di-HCl (H8) and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide HCl (HA1004). These PKA inhibitors had no effect on the PAH induction of the cyp1A1. Protein kinase A activity of cultured hepatocytes was specifically inhibited by H8 and HA1004 in a concentration-dependent manner, but not by H7, and there was an inverse correlation observed between potentiation of PAH-induced aldh3 gene expression and inhibition of specific PKA activity by the PKA inhibitors. The cAMP analog dibutyryl cAMP, the adenylate cyclase activator forskolin, and the protein phosphatase 1 and 2A inhibitor okadaic acid all dramatically inhibited both PAH induction and H8 potentiation of PAH induction of aldh3 expression but had no effect on induction of cyp1A1 expression in cultured hepatocytes. Both basal and PAH-dependent expression of a chloramphenicol acetyltransferase expression plasmid containing approximately 3.5 kilobase pairs of the 5'-flanking region of aldh3 (pALDH3.5CAT) were enhanced 3-4-fold by the PKA inhibitor H8 but not by the PKC inhibitor H7 (>20 microM). cAMP analogs, activators of PKA activity, or protein phosphatase inhibitors diminished expression of the reporter gene in a manner identical to the native gene in cultured rat hepatocytes. Using deletion analysis of the pALDH3.5CAT construct, we demonstrated the existence of a negative regulatory region in the 5'-flanking region between -1057 and -991 base pairs which appears to be responsible for the cAMP-dependent regulation of this gene under both basal and PAH-induced conditions. At least two apparently independent mechanisms which involve protein phosphorylation regulate aldh3 expression. One involves function of the Ah receptor which requires PKC protein phosphorylation to positively regulate both aldh3 and cyp1A1 gene expression and the other a cAMP-responsive process which allows PKA activity to negatively regulate expression of aldh3 under either basal or inducible conditions.
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PMID:cAMP-dependent negative regulation of rat aldehyde dehydrogenase class 3 gene expression. 901 60

The effect of cantharidin, a natural toxicant of blister beetles and a strong inhibitor of protein phosphatases types 1 and 2A, on luteinizing hormone (LH)-induced synthesis of steroidogenic acute regulatory (StAR) protein was studied in a serum-free culture of preovulatory follicles. StAR protein is a steroidogenic tissue-specific, hormone-induced, rapidly synthesized protein previously shown to be involved in the acute regulation of steroidogenesis, probably by promoting the transfer of cholesterol to the inner mitochondrial membrane and the cytochrome P450 side-chain cleavage (P450scc) enzyme. Treatment of preovulatory follicles dissected from ovaries of immature rats primed with pregnant mares' serum gonadotropin (10 IU) with LH for 24 h resulted in a dose-dependent increase in the level of StAR protein that reached a maximum at 100 ng LH/ml. This increase was associated with an increase in progesterone production. Treatment of follicles with increasing concentrations (10 - 1000 ng/ml) of cantharidin suppresssed LH (100 ng/ml)-induced StAR protein levels and progesterone production in a dose-dependent manner. The amount of P450scc protein and the conversion of 22R-hydroxycholesterol to progesterone were not affected by cantharidin. This indicates that cantharidin did not interfere with the activity of P450scc. Cantharidin also decreased StAR protein levels and progesterone production induced by the adenylate cyclase activator forskolin (10(-5) M) or a cAMP analog 8-Br-cAMP (0.5 mM). These results demonstrate that cantharidin inhibits the LH-induced StAR protein levels, and, thus, suggest that phosphoprotein phosphatase activity is required for the cAMP-protein kinase A-stimulated steroidogenic activity of the preovulatory follicle.
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PMID:Protein phosphatase inhibitor cantharidin inhibits steroidogenesis and steroidogenic acute regulatory protein expression in cultured rat preovulatory follicles. 1176 7

Lanthanides, also called rare-earth elements, are an interesting group of 15 chemically active, mainly trivalent, f-electronic, silvery-white metals. In fact, lanthanides are not as rare as the name implies, except for promethium, a radioactive artificial element not found in nature. The mean concentrations of lanthanides in the earth's crust are comparable to those of life-important elements like iodine, cobalt and selenium. Many lanthanide compounds show particular magnetic, catalytic and optic properties, and that is why their technical applications are so extensive. Numerous industrial sources enable lanthanides to penetrate into the human body and therefore detailed toxicological studies of these metals are necessary. In the liver, gadolinium selectively inhibits secretion by Kupffer cells and it decreases cytochrome P450 activity in hepatocytes, thereby protecting liver cells against toxic products of xenobiotic biotransformation. Praseodymium ion (Pr3+) produces the same protective effect in liver tissue cultures. Cytophysiological effects of lanthanides appear to result from the similarity of their cationic radii to the size of Ca2+ ions. Trivalent lanthanide ions, especially La3+ and Gd3+, block different calcium channels in human and animal cells. Lanthanides can affect numerous enzymes: Dy3+ and La3+ block Ca2+-ATPase and Mg2+-ATPase, while Eu3+ and Tb3+ inhibit calcineurin. In neurons, lanthanide ions regulate the transport and release of synaptic transmitters and block some membrane receptors, e.g. GABA and glutamate receptors. It is likely that lanthanides significantly and uniquely affect biochemical pathways, thus altering physiological processes in the tissues of humans and animals.
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PMID:Toxicological and cytophysiological aspects of lanthanides action. 1199

The effects of acute and subchronic exposure to mercury on the Cl- current (ICl) were investigated in cultured shark rectal gland (SRG) cells. The effects of intracellular accumulation of mercury on cytochrome P450 (P450) were also assessed. Bath perfusion of a cocktail solution containing forskolin, 1-isobutyl-3-methylxanthine, and 8-bromoadenosine monophosphate enhanced ICl. Addition of 10 microM HgCl2 significantly inhibited the cAMP-activated ICl (p < 0.05, n = 11). Intracellular dialysis with ATP gamma S did not prevent the inhibitory effect of mercury on ICl. In contrast, incubation of SRG cells with 10 microM HgCl2 for 48 hrs markedly increased ICl (p < 0.01, n = 12). Dephosphorylation of the channel by intracellular dialysis with phosphatase I and II abolished the mercury-incubated increase in ICl. The P450-mediated metabolite of arachidonic acid, 11,12-epoxyeicosatrienoic acid (11,12-EET), significantly increased ICl. However, application of 11,12-dihydroxyeicosatrienoic acid (11,12-DHT) did not alter ICl. Mercury incubation for 48 hrs did not alter the protein expression of Cl- channels, but caused an induction of CYP1A1 in cultured SRG cells. In addition, co-incubation of SRG cells with mercury and the P450 inhibitor clotrimazole prevented the mercury-incubated increase in ICl. Our results demonstrate that acute and subchronic application of mercury has opposing effects on ICl in cultured SRG cells. The acute effect of mercury on ICl may result from mercury blockade of Cl- channels. The subchronic effect of mercury on ICl may be due to an induction of P450 CYP1A1 and its mediated metabolites, but not due to an over-expression of Cl- channels.
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PMID:Intracellular accumulation of mercury enhances P450 CYP1A1 expression and Cl- currents in cultured shark rectal gland cells. 1217 17

Everolimus is an immunosuppressive macrolide bearing a stable 2-hydroxyethyl chain substitution at position 40 on the sirolimus (rapamycin) structure. Everolimus, which has greater polarity than sirolimus, was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase its oral bioavailability. Everolimus has a mechanism of action similar to that of sirolimus. It blocks growth-driven transduction signals in the T-cell response to alloantigen and thus acts at a later stage than the calcineurin inhibitors ciclosporin and tacrolimus. Everolimus and ciclosporin show synergism in immunosuppression both in vitro and in vivo and therefore the drugs are intended to be given in combination after solid organ transplantation. The synergistic effect allows a dosage reduction that decreases adverse effects. For the quantification of the pharmacokinetics of everolimus, nine different assays using high performance liquid chromatography coupled to an electrospray mass spectrometer, and one enzyme-linked immunosorbent assay, have been developed. Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3-1.8 hours. Steady state is reached within 7 days, and steady-state peak and trough concentrations, and area under the concentration-time curve (AUC), are proportional to dosage. In adults, everolimus pharmacokinetic characteristics do not differ according to age, weight or sex, but bodyweight-adjusted dosages are necessary in children. The interindividual pharmacokinetic variability of everolimus can be explained by different activities of the drug efflux pump P-glycoprotein and of metabolism by cytochrome P450 (CYP) 3A4, 3A5 and 2C8. The critical role of the CYP3A4 system for everolimus biotransformation leads to drug-drug interactions with other drugs metabolised by this cytochrome system. In patients with hepatic impairment, the apparent clearance of everolimus is significantly lower than in healthy volunteers, and therefore the dosage of everolimus should be reduced by half in these patients. The advantage of everolimus seems to be its lower nephrotoxicity in comparison with the standard immunosuppressants ciclosporin and tacrolimus. Observed adverse effects with everolimus include hypertriglyceridaemia, hypercholesterolaemia, opportunistic infections, thrombocytopenia and leucocytopenia. Because of the variable oral bioavailability and narrow therapeutic index of everolimus, blood concentration monitoring seems to be important. The excellent correlation between steady-state trough concentration and AUC makes the former a simple and reliable index for monitoring everolimus exposure. The target trough concentration of everolimus should range between 3 and 15 microg/L in combination therapy with ciclosporin (trough concentration 100-300 microg/L) and prednisone.
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PMID:Clinical pharmacokinetics of everolimus. 1474 18

Everolimus is a derivative of sirolimus, a macrocyclic lactone, originally isolated from Streptomyces hygroscopicus. Both everolimus and sirolimus have a similar mechanism of action, exerting potent inhibition of growth factor-induced proliferation of lymphocytes, as well as other hematopoietic and nonhematopoietic cells of mesenchymal origin. Each agent complexes with the FK506 binding protein 12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G1-S phase cell cycle arrest. Safety and efficacy have been documented in large-scale, blinded, randomized, international clinical renal and cardiac transplant trials. Everolimus is more hydrophilic, exhibits a shorter elimination half-life (approximately 30 hours), and demonstrates greater relative bioavailability compared to sirolimus. However, similar to the calcineurin inhibitors and sirolimus, everolimus is biotransformed by the cytochrome P450, 3A4 isozyme. Also similar to sirolimus, clinical experiences identified biologically relevant side effects including hyperlipidemia and exacerbation of cyclosporine (CsA)-associated nephrotoxicity. However, also similar to sirolimus, accumulating evidence suggests that the hyperlipidemia can be controlled and the CsA-associated renal effects appear reduced with a low incidence of acute rejection when everolimus is administered in combination with reduced CsA doses. The experience using everolimus in cardiac transplantation has also provided potentially important insights into the consequences of antiproliferative effects on vascular smooth muscle cells and fibroblasts where reduction in intimal expansion was identified by intravascular coronary ultrasound examination among those patients receiving everolimus. Therefore, available results suggest that the introduction of everolimus as the newest TOR inhibitor should enhance therapeutic options for immunosuppression after organ transplantation.
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PMID:The evolving experience using everolimus in clinical transplantation. 1504 95

The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients. Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 'acceptable' ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immunosuppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.
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PMID:Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. 1524 95

Pregnane X receptor (PXR, NR1I2) regulates the inducible expression of the 3A sub-family of cytochrome P450 genes (CYP3A). CYP3A enzymes are responsible for the oxidative metabolism of a wide array of endobiotic and xenobiotic compounds. Hepatic CYP3A gene expression is rapidly down-regulated during inflammation and sepsis. There are twelve protein kinase C (PKC) isoforms, classified into three subfamilies according to the structure of the N-terminal regulatory domain and their sensitivity to calcium and diacylglycerol. It is now well accepted that cytokine stimulation of hepatocytes increases intracellular PKC activity during inflammation and sepsis. We show here that protein kinase C alpha (PKC alpha) and phorbol ester-dependent PKC signaling dramatically repressed PXR activity in both, cell-based reporter gene assays and in hepatocytes. Moreover, treatment with the protein phosphatase PP1/PP2A inhibitor okadaic acid (OA) totally abolished PXR activity in reporter gene assays and in cultured hepatocytes. In mammalian two-hybrid assays, treatment with phorbol 12-myristate 13-acetate (PMA) increased the strength of interaction between PXR and the nuclear receptor co-repressor protein (NCoR). Treatment with PMA also abolished the ligand-dependent interaction between PXR and the steroid receptor co-activator 1 protein (SRC1). Our findings suggest that activation of the protein kinase C signaling pathway represses PXR activity through alterations in PXR-protein co-factor complexes, possibly through direct alterations in the phosphorylation status of one or all of these proteins. In addition, our data potentially provide important insights into the molecular mechanism of the repression of hepatic CYP3A gene expression that occurs during the inflammatory response.
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PMID:Repression of PXR-mediated induction of hepatic CYP3A gene expression by protein kinase C. 1571 Mar 63

With the use of powerful immunosuppressive drugs, organ transplantation has become the treatment of choice for many cases of end-stage chronic organ failure. The calcineurin inhibitors, cyclosporine and tacrolimus, which are the backbone of current immunosuppressive regimens, may be difficult to use because of the large interindividual variability of their pharmacokinetic characteristics and a narrow therapeutic index. Since cytochrome P450 (CYP) 3A4 and CYP3A5 are both involved in their metabolism, the consequences of the polymorphism of these enzymes were studied. It has been recently shown that the CYP3A5*3 polymorphism is associated with both the pharmacokinetics and pharmacodynamic consequences of tacrolimus. The association between the CYP3A4 and CYP3A5 polymorphisms and cyclosporine pharmacokinetics is more questionable. It is important to test these initial results prospectively to improve the individualized use of these drugs.
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PMID:Cytochrome P450 3A polymorphisms and immunosuppressive drugs. 1572 4


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