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:3.1.27.4 (ribonuclease)
6,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-two-day-old fetal and five-day-old newborn rats were pretreated with phenobarbital and its hydroxylated metabolites. Drug-metabolizing enzymes (cytochrome P450, epoxide hydrolase, UDP-glucuronosyltransferase, and glutathione-S-transferase) and microsomal ribonuclease were not modified in fetuses treated with 80 or 400 mg . kg-1 of p-hydroxyphenobarbital, in spite of its accumulation in fetal liver. At fetal age, phenobarbital was a poor inducer of drug-metabolizing enzymes. In five-day-old newborns, p-hydroxyphenobarbital provoked a proliferation of endoplasmic reticulum without enzyme induction, whereas phenobarbital induced some drug-metabolizing enzymes. Thus, the effects of p-hydroxyphenobarbital and phenobarbital are retained in five-day-old rats, but undetectable in the fetuses.
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PMID:Comparison of the effects of phenobarbital and its hydroxylated metabolites on drug-metabolizing enzymes during ontogenesis. 681 Feb 95

In the corpus luteum, prostaglandin F2 alpha (PGF2 alpha) appears to be a physiological agent with both antisteroidogenic and luteolytic actions. It is hypothesized that the antisteroidogenic action of PGF2 alpha acts through altered transport of cholesterol to the mitochondrial cytochrome P450 side-chain cleavage enzyme (P450scc). However, the effect of PGF2 alpha on the expression of the putative cholesterol transport protein, sterol carrier protein-2 (SCP2; 13.2 kilodaltons), has not been examined. In this study, the decline in serum progesterone after PGF2 alpha injection was examined in parallel with altered ovarian SCP2, P450scc, and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) protein and messenger RNA (mRNA) levels. Rats (28 days old) were treated with 8 IU PMSG to induce follicular development and ovulation. Ten days after ovulation, animals were treated with PGF2 alpha (single or multiple injections; 100-250 micrograms each) or left untreated. Ovarian SCP2, P450scc, and 3 beta HSD protein and mRNA levels were examined 0 (time zero), 4, and 8 h post-PGF2 alpha treatment using Western and Northern blot analysis. SCP2 mRNA levels were also examined using a highly sensitive ribonuclease protection assay that detects a 429-base pair SCP2-mRNA specific sequence. The results indicate that serum progesterone was significantly reduced 4 and 8 h after PGF2 alpha injections (P < 0.001; n = 6/time point). The decline in progesterone paralleled a 50-60% reduction in 3 beta HSD protein and mRNA levels by 4 h post-PGF2 alpha. Protein and mRNA levels for 3 beta HSD returned to control values by 8 h post-PGF2 alpha treatment. P450scc expression was also reduced at 4 h (44-54%), but by 8 h, both protein and mRNA levels had increased above the normal control levels (P < 0.02). In contrast, the 0.8-kilobase SCP2-specific mRNA transcript was reduced to 50% and 80% of the pre-PGF2 alpha treatment level at 4 and 8 h, respectively (P < 0.01). SCP2 ribonuclease protection assay analysis also indicated that SCP2 mRNA levels were reduced 65% (P < 0.03) and 85% (P < 0.01) by 4 and 8 h post-PGF2 alpha treatment compared to those in time zero ovarian tissue. Consistent with the loss of SCP2 mRNA expression, Western blot analysis indicated that a 15-kilodalton SCP2-immunoreactive protein (presumably the pro-SCP2 form) was significantly reduced or absent in the PGF2 alpha treated animals (P < 0.04).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Prostaglandin F2 alpha mediates ovarian sterol carrier protein-2 expression during luteolysis. 758 30

In cattle, a dramatic increase in plasma estradiol occurs during the short 2- to 3-day follicular phase. The objective of this study was to investigate the molecular mechanisms that mediate this critical change, specifically whether increases in the steroidogenic ability of granulosa and thecal cells of the preovulatory follicle are associated with increases in the levels of messenger RNA (mRNA) for steroidogenic enzymes. Luteolysis and a follicular phase were induced cycling Holstein heifers (n=15) by injection of a luteolytic dose of prostaglandin F2 alpha (PGF 2 alpha) on day 6 or 7 of the estrous cycle (day 0 = estrus), and preovulatory follicles were obtained at three stages of differentiation (0, 12, or 24 h post-PGF2 alpha treatment). To assess developmental changes in steroidogenesis in vivo, estradiol and androstenedione were measured in follicular fluid and in culture medium after a 3-h incubation of granulosa and thecal cells in defined medium with or without gonadotropins. To determine whether changes in mRNA for steroidogenic enzymes are associated with changes in follicular steroidogenesis, levels of mRNA for cytochrome P450 side-chain cleavage (P450scc), 3 beta-hydroxysteroid dehydrogenase (3 beta HSD), cytochrome P450 17 alpha-hydroxylase, and cytochrome P450 aromatase (P450arom) were measured in thecal and granulosa cells using ribonuclease protection assays. Concentrations of estradiol in follicular fluid were relatively high at time zero, increased significantly by 12 h, and increased further by 24 h post-PGF2 alpha treatment. However, the aromatizing activity of granulosa cells was high at the time of PGF2 alpha injection and did not increase significantly during the first 24 h after the initiation of luteolysis. The aromatizing activity of granulosa cells was reflected in levels of mRNA for P450arom, which was relatively abundant in granulosa cells obtained before luteolysis and did not increase further during the first 24 h of the follicular phase. Concentrations of androstenedione were virtually undetectable in follicular fluid at time zero and had increased dramatically by 12 and 24 h post-PGF2 alpha treatment. Similarly, thecal cells isolated at 24 h secreted 3-fold more androstenedione than cells isolated at the time of PGF2 alpha injection. Androstenedione production by thecal cells in response to LH was also markedly higher at 12 and 24 h than at the time of PGF2 alpha injection. Likewise; levels of mRNA for P450 17 alpha-hydroxylase increased significantly by 12 h post-PGF2 alpha treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differentiation of bovine preovulatory follicles during the follicular phase is associated with increases in messenger ribonucleic acid for cytochrome P450 side-chain cleavage, 3 beta-hydroxysteroid dehydrogenase, and P450 17 alpha-hydroxylase, but not P450 aromatase. 758 47

Detoxification of host plant defensive compounds by larval Lepidoptera is mediated by cytochrome P450 monooxygenases (P450s) such as CYP6B1, which is expressed in Papilio polyxenes (black swallowtail) larvae in response to xanthotoxin, a linear furanocoumarin. Baculovirus-mediated expression of two cloned CYP6B1 cDNAs in lepidopteran cell lines has demonstrated that CYP6B1 isozymes primarily metabolize the linear furanocoumarins, xanthotoxin and bergapten, and not angular furanocoumarins. To characterize the regulatory features of the CYP6B1 transcription unit, we have isolated the first full-length CYP6B1v3 genomic DNA clone from P. polyxenes. The open reading frame of this gene is interrupted by a single intron and is virtually identical to the previously characterized CYP6B1 cDNAs. Primer extension and ribonuclease protection analyses have localized the transcription initiation site to a point 28 nucleotides upstream from the AUG initiation codon. RNase protection analyses on RNA from larvae induced by linear and angular furanocoumarins indicate that transcription of the CYP6B1 gene is induced in insects significantly in response to xanthotoxin and only slightly in response to bergapten. Angular furanocoumarins, such as angelicin, which are not appreciably metabolized by the CYP6B1 gene product, do not significantly induce transcription of this gene. We conclude that this P450 gene is transcriptionally regulated in vivo by at least one of the substrates which the encoded protein metabolizes. Transient expression of CAT fusion constructs in transfected Sf9 lepidopteran cells demonstrates that nucleotides -1 to -838 upstream from the CYP6B1v3 transcription initiation site retain basal and xanthotoxin-inducible transcriptional activities in this heterologous cell line. These data clearly indicate that P. polyxenes has adapted to the presence of furanocoumarins in its host plants by evolving P450 isozymes and regulatory cascades which respond to specific toxins.
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PMID:Transcriptional regulation of the Papilio polyxenes CYP6B1 gene. 806 37

Regression of the CL causes a dramatic decrease in plasma progesterone levels. To test the hypothesis that the decrease in progesterone involves the down-regulation of mRNA encoding the steroidogenic enzymes, cytochrome P450 side-chain cleavage (P450scc) and/or 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), levels of plasma progesterone and luteal mRNA for P450scc and 3 beta-HSD were measured and correlated during induced luteolysis. Holstein heifers (n = 25) were injected with 25 mg prostaglandin F2 alpha (PGF2 alpha) on Day 6 or 7 of the estrous cycle (Day 0 = estrus) to induce luteal regression. To determine acute changes in plasma progesterone during luteolysis, jugular blood samples were obtained from 5 heifers hourly for 12 h, beginning immediately before injection of PGF2 alpha, and assayed for progesterone by RIA. A significant decrease in plasma progesterone levels was observed as early as 1 h after the PGF2 alpha injection (3.62 vs. 2.72 ng/ml, p < 0.05). Progesterone levels continued to decline with time through 12 h after administration of PGF2 alpha. The other 20 animals were ovariectomized at 0 (n = 6), 2 (n = 4), 12 (n = 4), or 24 (n = 6) h after PGF2 alpha. Levels of P450scc and 3 beta-HSD mRNA were determined in extracts of total luteal RNA by ribonuclease (RNase) protection assay. By 2 h after PGF2 alpha, 3 beta-HSD mRNA levels had decreased by about 40% as compared with levels at time 0 (p < 0.05), and a further significant decrease occurred between 2 and 12 h.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in levels of messenger ribonucleic acid for cytochrome P450 side-chain cleavage and 3 beta-hydroxysteroid dehydrogenase during prostaglandin F2 alpha-induced luteolysis in cattle. 814 50

In humans the last steps in the synthesis of aldosterone and cortisol rely on the activity of two cytochrome P450 genes termed CYP11B2 (aldosterone synthase; P450aldo) and CYP11B1 (11 beta hydroxylase; P450cl1). The mechanisms which lead to differential expression of these two genes within the adrenal cortex are not well-defined. The human adrenocortical cell line. H295R, was utilized in this study to examine the intracellular second messenger pathways regulating expression of P450aldo and P450c11. using specific ribonuclease protection assays. Treatment of H295R cells with angiotensin II or potassium (K+) caused a time-dependent induction in the level of P450aldo transcripts. While K+ treatment was more specific for the induction of P450aldo mRNA, treatment with angiotensin II increased levels of both P450aldo and P450c11 transcripts. To define the second messenger systems which influence transcript levels for these enzymes, the effects of agonists of the protein kinase A, protein kinase C, and calcium pathways were tested on the expression of P450aldo and P450c11. Activation of the protein kinase A pathway by the agonists, dibutyryl cAMP or forskolin, preferentially increased the P450c11 transcript to a greater degree than P450aldo. Interestingly, activation of the protein kinase C pathway by tetradecanoylphorbol acetate (TPA) did not alter transcripts for either P450aldo or P450c11. The calcium channel agonist BAYK 8644 mimicked the effects of K+ by increasing the transcript for P450aldo. However, the calcium channel blocker nifedipine attenuated the stimulatory effects of angiotensin II and K+ on the levels of P450aldo. However, the calcium channel blocker nifedipine attenuated the stimulatory effects of angiotensin II and K+ on the levels of P450aldo transcripts without affecting the stimulatory effect of dbcAMP. This study demonstrates that the protein kinase A pathway preferentially induces P450c11 mRNA over that of P450aldo. In addition, pharmacologic agents that affect calcium levels provide evidence for an additional regulatory mechanism in modulating the expression of P450aldo. This is of importance since the major physiologic regulators of aldosterone secretion, angiotensin II and K+ are able to increase intracellular calcium but have little effect on intracellular cAMP levels.
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PMID:Differential regulation of 11 beta-hydroxylase and aldosterone synthase in human adrenocortical H295R cells. 886 69

Interferon-gamma (IFNgamma) is an immunomodulating cytokine that has profound effects on reproductive function. IFNgamma inhibits steroidogenesis both in vivo and in vitro. The mechanism by which IFNgamma inhibits Leydig cell steroidogenesis remains unclear. In the present study, we evaluated the effect of IFNgamma on the expression and regulation of the steroidogenic acute regulatory protein (StAR) gene in primary cultures of rat Leydig cells. StAR facilitates the efficient production of steroid hormone by regulating the translocation of cholesterol from the outer to the inner mitochondrial membrane, the site of the cytochrome P450 side-chain cleavage (P450scc) enzyme system that converts cholesterol to pregnenolone. IFNgamma inhibited hCG-induced StAR messenger RNA (mRNA) levels in a dose-dependent manner. The addition of IFNgamma in a concentration of 500 U/ml decreased hCG-induced 3.8- and 1.7-kilobase StAR mRNA by 78% and 70%, respectively. IFNgamma also reduced hCG-stimulated P450scc mRNA levels by 69%. The inhibitory effects of IFNgamma on StAR mRNA levels were confirmed by ribonuclease protection assay. As early as 12 h after the addition of IFNgamma, hCG-induced StAR mRNA levels decreased by more than 44%. To evaluate the effects of IFNgamma on StAR protein levels, Western blot analyses were performed. hCG in a concentration of 10 ng/ml increased StAR protein by 5.6-fold. Treatment of Leydig cells with IFNgamma (500 U/ml) decreased hCG-induced StAR protein by 44%. In contrast, interleukin-1 and murine tumor necrosis factor-alpha reduced hCG-induced P450scc mRNA expression without inhibiting StAR mRNA or protein levels. In conclusion, IFNgamma inhibits Leydig cell steroidogenesis by down-regulating StAR gene expression and protein production.
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PMID:Interferon-gamma inhibits the steroidogenic acute regulatory protein messenger ribonucleic acid expression and protein levels in primary cultures of rat Leydig cells. 956 25

Insulin-like growth factor-I (IGF-I) plays an essential role in reproductive function. Leydig cells express specific IGF-I receptors, and IGF-I enhances human chorionic gonadorphin (hCG)-induced testosterone formation. In the present study, we evaluate the effect of IGF-I on the gene expression and protein levels of steroidogenic acute regulatory protein (StAR), the rate-limiting step in steroidogenesis. StAR mRNA is expressed in rat Leydig cells as two major transcripts of 3.8 and 1.7 kb. StAR mRNA levels (both 3.8 and 1.7 kb) were markedly induced about 20-fold by hCG (10 ng/mL). Concomitant addition of IGF-I (50 or 100 ng/mL) and hCG (10 ng/mL) resulted in significant increases in StAR and cytochrome P450 side-chain cleavage (P450scc) mRNA levels, whereas lower doses of IGF-I (1 or 10 ng/ mL) had small effects. Synergistic effects of IGF-I and hCG on StAR mRNA levels were confirmed by ribonuclease protection assay (RPA). IGF-I (100 ng/mL) enhanced hCG- and 20 OH-cholesterol + hCG-induced testosterone formation, whereas the conversions of pregnenolone, 17-OH pregnenolone, dehydroepiandrosterone, and androstenedione to testosterone were not affected. This suggests that the major effect of IGF-I is at the steps of StAR and P450scc, whereas other steroidogenic enzymes are not affected. To evaluate whether increased StAR mRNA levels induced by IGF-I and hCG are associated with increased StAR protein levels, we carried out Western blot analyses. Basal StAR protein levels were low after 24 h in culture. hCG (10 ng/mL) increased StAR protein by 4.5-fold. In the presence of IGF-I (100 ng/mL), hCG-induced StAR protein levels were further increased. In conclusion, our present study demonstrated that IGF-I enhances Leydig cell steroidogenesis by upregulating hCG-induced StAR gene expression and protein production.
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PMID:Upregulation of human chorionic gonadotrophin-induced steroidogenic acute regulatory protein by insulin-like growth factor-I in rat Leydig cells. 966 48

A cDNA encoding a cytochrome P450 enzyme was isolated from a cDNA library of the corpora allata (CA) from reproductively active Diploptera punctata cockroaches. This P450 from the endocrine glands that produce the insect juvenile hormone (JH) is most closely related to P450 proteins of family 4 and was named CYP4C7. The CYP4C7 gene is expressed selectively in the CA; its message could not be detected in the fat body, corpora cardiaca, or brain, but trace levels of expression were found in the midgut and caeca. The levels of CYP4C7 mRNA in the CA, measured by ribonuclease protection assays, were linked to the activity cycle of the glands. In adult females, CYP4C7 expression increased immediately after the peak of JH synthesis, reaching a maximum on day 7, just before oviposition. mRNA levels then declined after oviposition and during pregnancy. The CYP4C7 protein was produced in Escherichia coli as a C-terminal His-tagged recombinant protein. In a reconstituted system with insect NADPH cytochrome P450 reductase, cytochrome b5, and NADPH, the purified CYP4C7 metabolized (2E,6E)-farnesol to a more polar product that was identified by GC-MS and by NMR as (10E)-12-hydroxyfarnesol. CYP4C7 converted JH III to 12-trans-hydroxy JH III and metabolized other JH-like sesquiterpenoids as well. This omega-hydroxylation of sesquiterpenoids appears to be a metabolic pathway in the corpora allata that may play a role in the suppression of JH biosynthesis at the end of the gonotrophic cycle.
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PMID:A cytochrome P450 terpenoid hydroxylase linked to the suppression of insect juvenile hormone synthesis. 978 9

Young animals adapt to a low calcium diet by increasing renal production of 1,25-dihydroxyvitamin D [1,25(OH)2D], the active metabolite of vitamin D. However, the capacity of adult animals to adapt is markedly diminished. With the recent cloning of the cytochrome P450 component (CYP1a) of the renal 1-hydroxylase enzyme complex, it is now possible to determine directly the effect of dietary calcium and maturation on the expression of renal 1-hydroxylase. Using a ribonuclease protection assay, it was found that feeding a low Ca diet markedly increased renal CYP1a mRNA levels in young rats. However, feeding this diet to adult rats produced an increase in CYP1a mRNA that was only 10% that of the young rats. These studies demonstrate that a low calcium diet increases renal 1,25-dihydroxyvitamin D production in young animals but not in adult animals by increasing CYP1a expression. Since the low calcium diet increased plasma parathyroid hormone levels to similar levels in both age groups, this suggests that in the adult there is a renal refractoriness to parathyroid hormone.
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PMID:Capacity of a low calcium diet to induce the renal vitamin D 1a-hydroxylase is decreased in adult rats. 1004 79


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