Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to characterize the role of the endothelium in angiotensin II-desensitization and its mechanisms of action. Rabbit aortic rings were exposed to increasing doses of angiotensin II (Ang II, 10(-9) to 2.5 x 10(-6)) to generate two cumulative dose-response curves (CDRC I and II). A 50-min interval separated CDRC I and II. Desensitization was observed at all doses in unrubbed aortic tissue and at lower doses in rubbed aortic tissue. Tachyphylaxis was greater in arteries with endothelium. Treatment of intact rings with L-N(G)-nitroarginine methyl ester (L-NAME, 10(-4) M) did not prevent this phenomenon. However, indomethacin (10(-5) M) and miconazol (10(-6) M) attenuated Ang II-desensitization. Treatment of unrubbed rings with nifedipine (10(-6) M) and cromakalim (10(-6) M) inhibited the effect of indomethacin. To confirm the involvement of K+ channels, unrubbed and rubbed aortic rings were treated with the K(Ca2+) blockers apamin (10(-7) M), tetraethylammonium (TEA, 10(-3) M), and iberiotoxin (10(-8) M), and the K(ATP) blocker glibenclamide (10(-5) M). In both arteries apamin, TEA, and glibenclamide abolished the tachyphylaxis without changes in the maximal response. Iberiotoxin diminished Ang II-desensitization in rubbed but not unrubbed arteries. Results from this study suggest that Ang II-desensitization involves endothelium-dependent and -independent mechanisms. Endothelium-dependent desensitization could be mediated by a cyclooxygenase-cytochrome P450 product, which could act by increasing K(Ca2+) channel activity.
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PMID:Endothelium-dependent desensitization to angiotensin II in rabbit aorta: the mechanisms involved. 1143 May 85

The cytochrome P450 gene CYP2H1 is highly induced by phenobarbital in chick embryo hepatocytes. Recent studies have established that the orphan nuclear receptor CAR plays a critical role in the induction mechanism. Here, we show that a high concentration of the potent glucocorticoid and progesterone receptor antagonist RU486 almost completely blocks phenobarbital-induced accumulation of CYP2H1 mRNA in hepatocytes yet has no effect on basal expression. In marked contrast, CYP2H1 mRNA induced by the phenobarbital-type inducers glutethimide and 2-allylisopropylacetamide is not affected by RU486. RU486 inhibition is not mediated through the glucocorticoid or progesterone receptors. Transient transfection studies showed that RU486 does not repress through activation of the orphan receptor PXR and subsequent competition with CAR for binding to the upstream drug-responsive 556-base-pair enhancer. Additionally, none of the known functional transcription factor binding sites found in the enhancer region was a target of RU486 inhibition. Using an artificial construct containing multiple CAR binding sites, we also established that RU486 has no direct effect on the activity of exogenously expressed CAR. There is no evidence that phenobarbital binds to CAR; we propose that RU486 inhibits phenobarbital induction, either by interfering with a phenobarbital-dependent mechanism responsible for nuclear import of CAR or with the metabolism of phenobarbital to the true inducer. Whether a novel nuclear receptor that binds RU486 at high concentrations plays a role in the inhibitory action of RU486 is an interesting possibility.
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PMID:The antiglucocorticoid RU486 inhibits phenobarbital induction of the chicken CYP2H1 gene in primary hepatocytes. 1145 14

This study determined the contribution of prostanoids, cytochrome P450 (CP450) 4A enzyme metabolites of arachidonic acid, and other potential mediators of hypoxic dilation of isolated rat skeletal muscle resistance arteries. Gracilis arteries (GA) were viewed via television microscopy and dilator responses to hypoxia (reduction in superfusate and perfusate PO2 from approximately 145 to approximately 40 mm Hg) were measured with a video micrometer. Hypoxic dilation of gracilis arteries was severely impaired by either endothelium removal or cyclooxygenase inhibition with indomethacin, but not by nitric oxide synthase inhibition with L-NAME. Treatment of GA with 17-octadecynoic acid (17-ODYA) alone to inhibit CP450 4A enzymes significantly reduced hypoxic dilation from control levels. Treatment of vessels with N-methylsulfonyl-6-(2-proparglyoxyphenyl)hexanoic acid (MS-PPOH) to inhibit the production of epoxyeicosatrienoic acids (EETs) did not alter hypoxic dilation, although treatment with dibromo-dodecenyl-methylsulfimide (DDMS) to inhibit 20-hydroxyeicosatetraenoic acid (20-HETE) production had similar effects as 17-ODYA. Treatment of GA with 6(Z),15(Z)-20-HEDE, a competitive antagonist of the actions of 20-HETE, mimicked the effects of 17-ODYA and DDMS treatment on hypoxic dilation. These results suggest that hypoxic dilation of skeletal muscle resistance arteries primarily represents the effects of enhanced prostanoid release from vascular endothelium, although a contribution of reduced 20-HETE production via CP450 omega-hydroxylase enzymes also regulates hypoxic dilation of these vessels.
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PMID:Relative contributions of cyclooxygenase- and cytochrome P450 omega-hydroxylase-dependent pathways to hypoxic dilation of skeletal muscle resistance arteries. 1145 1

It has been shown recently that androstenol and androstanol could modulate gene expression through the nuclear orphan receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor). Although, in the pig, androstenol is produced in high amounts and is active as a pheromone, its role in the human is ill defined. Androstenol possesses a structure similar to that of androgens, with the exception that it does not possess an oxygen at position 17 that is crucial for androgenic and estrogenic activity. It has been shown that human and boar testis homogenates could produce androstenol, but details of the biosynthetic pathway had not yet been elucidated. It has also been shown recently that androstenol could modulate the activity of CAR and PXR and the expression of some cytochrome P450 drug-metabolizing enzymes. We wanted to determine the precise biosynthetic pathway of androstenol and other closely related steroids. Using transformed human embryonic kidney (HEK-293) cells that stably express 3 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase, we have shown that these enzymes are able to efficiently transform the precursor 5,16-androstadien-3 beta-ol into androstenol. We thus provided evidence that androstenol, the ligand for CAR and PXR, is produced by the biosynthetic pathway of sex steroids.
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PMID:Comparative biosynthetic pathway of androstenol and androgens. 1145 60

Ca2+-dependent secretagogues evoke only a transient Cl- secretion in intestinal epithelia, although they induce a prolonged increase in the intracellular Ca2+ concentration, suggesting that they may exert an additional antisecretory action. In order to study the mechanism of this antisecretory effect, Cl- secretion, measured as the increase in short-circuit current (Isc), was evoked by carbachol in the absence and presence of different inhibitors. Neither a calmodulin antagonist, calmidazolium, nor different inhibitors of the nitric oxide (NO) pathway, i.e. Nomega-nitro-L-arginine (L-NNA) and Nomega-nitro-L-arginine methylester (L-NAME), affected the carbachol-induced Isc. However, inhibition of phospholipases A2 (PLA2) by quinacrine or arachidonyltrifluoromethyl ketone (AACOCF3) enhanced the Isc response evoked by carbachol, suggesting a role of fatty acids in the downregulation of anion secretion. Neither econazole, a cytochrome P450 inhibitor, nor nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenases, mimicked the action of the PLA2 blockers. Conversely, short- or medium-chain fatty acids inhibited the carbachol- and forskolin-induced Isc with caprate (C10:0) being the most efficient water-soluble fatty acid. This fatty acid inhibited a Cl- current, which was driven across the apical membrane by a serosally to mucosally directed Cl- gradient after depolarization of the basolateral membrane. A second action site of fatty acids seems to be the basolateral membrane. After permeabilization of the apical membrane with the ionophore nystatin, a mucosally to serosally directed K+ gradient induced a K+ current, which was also inhibited by caprate. These results indicate that carbachol not only acts as a secretagogue but at the same time initializes downregulation by increasing the intracellular concentration of fatty acids, a mechanism limiting the resulting Cl- secretion.
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PMID:Fatty acids inhibit anion secretion in rat colon: apical and basolateral action sites. 1151 Aug 94

A turpentine-induced inflammatory reaction (TIIR) down-regulates multiple isoforms of hepatic cytochrome P450 (P450) and increases microsomal lipid peroxidation. Since the synthesis of nitric oxide (NO*) is stimulated by inflammatory reactions, and NO* can depress the P450, it was of interest to investigate in vivo whether L-NAME and theophylline, by its anti-inflammatory properties, could prevent the depression of P450 caused by a TIIR. Control and rabbits with a TIIR received L-NAME for 72 h, and the activity of P450 was assessed in vivo and in vitro. In vivo, TIIR reduced theophylline systemic clearance by 50% (p<0.05), P450 total content by 67%, and the amount of CYP1A1/2 proteins by around 60% (p<0.05). L-NAME partially prevented the decrease in theophylline systemic clearance and in P450 total content, as well as the increase in lipid peroxidation; however, L-NAME did not hinder CYP1A1/2 proteins down-regulation. L-NAME did not modify the in vitro ability of the serum of rabbits with TIIR to decrease P450 activity, suggesting that the effect of L-NAME is not associated to a decrease in serum mediators. As assessed by the concentration in seromucoids, theophylline did not modify the severity of the inflammatory reaction, nor did it prevent the decrease in P450 activity. In conclusion, a TIIR down-regulates and reduces P450 activity, decrease that is at least in part mediated by NO*; theophylline does not prevent TIIR-induced P450 decrease in activity.
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PMID:L-NAME prevents in vivo the inactivation but not the down-regulation of hepatic cytochrome P450 caused by an acute inflammatory reaction. 1155 17

Although cytochrome P450 2C9 (CYP2C9) is a major CYP expressed in the adult human liver, its mechanism of regulation is poorly known. In previous work, we have shown that CYP2C9 is inducible in primary human hepatocytes by xenobiotics including dexamethasone, rifampicin, and phenobarbital. The aim of this work was to investigate the molecular mechanism(s) controlling the inducible expression of CYP2C9. Deletional analysis of CYP2C9 regulatory region (+21 to -2088) in the presence of various hormone nuclear receptors suggested the presence of two functional response elements, a glucocorticoid receptor-responsive element (-1648/-1684) and a constitutive androstane receptor-responsive element (CAR, -1783/-1856). Each of these were characterized by co-transfection experiments, directed mutagenesis, gel shift assays, and response to specific antagonists RU486 and androstanol. By these experiments we located a glucocorticoid-responsive element imperfect palindrome at -1662/-1676, and a DR4 motif at -1803/-1818 recognized and transactivated by human glucocorticoid receptor and by hCAR and pregnane X receptor, respectively. Identification of these functional elements provides rational mechanistic basis for CYP2C9 induction by dexamethasone (submicromolar concentrations), and by phenobarbital and rifampicin, respectively. CYP2C9 appears therefore to be a primary glucocorticoid-responsive gene, which in addition, may be induced by xenobiotics through CAR/pregnane X receptor activation.
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PMID:Transcriptional regulation of CYP2C9 gene. Role of glucocorticoid receptor and constitutive androstane receptor. 1167 85

The products of the cytochrome P450 (CYP) genes play an important role in the detoxification of xenobiotics and environmental contaminants, and many foreign chemicals or xenobiotics can induce their expression. We have previously shown that the nuclear hormone receptor CAR (Constitutive Androstane Receptor, NR113) mediates the well studied induction of CYP2B10 gene expression by phenobarbital (PB) and 1, 4-bis-[2-(3, 5,-dichloropyridyloxy)] benzene (TCPOBOP). We have used the CAR knockout mouse model to explore the broader functions of this xenobiotic receptor. In addition to the liver, CAR is expressed in the epithelial cells of the villi in the small intestine, and this expression is required for CYP2B10 induction in response to PB and TCPOBOP in those cells. In agreement with previous observations that CAR can bind to regulatory elements in CYP3A genes, CAR is also required for induction of expression of CYP3A11 in response to both PB and TCPOBOP in liver. In males, CAR is also required for induction of liver CYP2A4 expression. In wild type animals, pretreatment with the CAR inverse agonist androstenol blocks the response of both the CYP2B10 and CYP3A11 genes to PB and TCPOBOP, and decreases basal CYP3A11 expression. CAR is also required for the response of CYP2B10 to several additional xenobiotic inducers, including chlorpromazine, clotrimazole and dieldrin, but not dexamethasone, an agonist for both the xenobiotic receptor PXR (Pregnane X Receptor NR112) and the glucocorticoid receptor. Chlorpromazine induction of CYP3A11 is also absent in CAR-deficient animals, but the responses to clotrimazole and dieldrin are retained, indicating that both of these inducers can also activate PXR (Pregnane X Receptor NR112). We conclude that CAR has broad functions in xenobiotic responses. Some are specific to CAR but others, including induction of the important drug metabolizing enzyme CYP3A, overlap with those of PXR.
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PMID:Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. 1204 74

Two orphan nuclear receptors, constitutive active (or androstane) receptor (CAR) and pregnane X receptor (PXR), are among the most important mediators of ligand-activated transcriptional induction of liver microsomal cytochrome P450 drug-metabolizing enzymes. CAR and PXR belong to the same NR1I receptor subfamily and show high sequence homology to each other. The vitamin D receptor (VDR) also belongs to the NR1I subfamily and has the second highest homology to CAR in the ligand binding domain. A 3D model of the ligand binding domain of human CAR (hCAR) was constructed based on the available X-ray structures of human PXR (hPXR) and VDR (hVDR). The model shows that the size of the ligand binding cavities of hCAR and hPXR are similar, but larger than that of hVDR. hPXR's capability of binding to extremely large ligands, such as rifampicin, implies that its binding cavity may be able to expand further through the flexibility of a surface loop. In contrast, hCAR does not have this loop so that its cavity cannot expand, suggesting that hCAR would not bind to the largest hPXR ligands. Docking calculations of selected ligands to hCAR, based on the structural model, are consistent with previously reported receptor binding data. The results from this study indicate that structural modeling will be a useful tool for understanding ligand binding to hCAR and for design of drugs free of hCAR-mediated enzyme induction.
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PMID:Insights from a three-dimensional model into ligand binding to constitutive active receptor. 1216 58

The mechanisms of vasorelaxation elicited by N(omega)-hydroxy-L-arginine (L-NOHA) and other compounds bearing a C=NOH function and the structural determinants governing this effect were investigated in rat aorta. L-NOHA, formamidoxime, five aromatic monosubstituted amidoximes, and one aromatic monosubstituted ketoxime elicited relaxation in endothelium-denuded rings. N-Hydroxyguanidine and substituted N-hydroxyguanidines were markedly less active. Relaxations induced by L-NOHA and by the most active studied compound, 4-chlorobenzamidoxime (ClBZA), were unmodified by the presence of endothelium. In endothelium-denuded rings, they were blunted by the NO scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (300 microM) and by the inhibitor of guanylyl-cyclase activation 1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one (1 microM). In addition, L-NOHA- and ClBZA both caused cGMP accumulation. L-Arginine, but not D-arginine (1 mM), antagonized the effect of L-NOHA but not ClBZA. Both L-NOHA- and ClBZA-induced relaxations were inhibited by the NAD(P)H-dependent enzymes inhibitor diphenyliodonium (30 microM) and the NAD(P)H-dependent reductases inhibitor 7-ethoxyresorufin (10 microM), but they were unmodified by the cytochrome P450 (P450) inhibitor proadifen (10 microM) and by the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 300 microM). These results show that L-NOHA and other compounds with a C=NOH function can cause endothelium-independent relaxation in the rat aorta. They suggest that activation of guanylyl cyclase and NO formation is implicated in relaxation and that a 7-ethoxyresorufin-sensitive NAD(P)H-dependent pathway is involved. On one hand, L-NOHA and amidoximes may be useful tools for characterizing this pathway in blood vessels and, on the other, may offer a novel approach for treating vascular diseases with impaired endothelial NO activity.
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PMID:Involvement of NO in the endothelium-independent relaxing effects of N(omega)-hydroxy-L-arginine and other compounds bearing a C=NOH function in the rat aorta. 1238 69


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