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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In pregnant mares, eCG stimulates luteal androgen and estrogen production, increasing plasma concentrations 2- to 3-fold. To study how these changes are regulated, we examined the expression of mRNA for the steroidogenic enzymes 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), cytochrome P450 17 alpha-hydroxylase/17,20-lyase (P450 17 alpha), and cytochrome P450 aromatase (P450arom) in equine primary corpora lutea using Northern blot analyses. Three equine specific cDNAs were generated by reverse transcriptase polymerase chain reaction. When compared to human, bovine, and rat sequences, the nucleotide identities were 82%, 84%, and 76%, respectively, for 3 beta-HSD cDNA (843 base pairs [bp]); 79%, 80% and 66% for P450(17) alpha cDNA (541 bp); and 80%, 83% and 75% for P450arom cDNA (289 bp). The P450(17) alpha cDNA sequence demonstrated 99.6% nucleotide identity with the previously published sequence for equine testicular P450(17) alpha. Luteal tissue samples were collected at three times: diestrus (Days 8-10), early pregnancy before the onset of eCG secretion (Days 29-35), and early pregnancy after the onset of eCG secretion (Days 42-45). Although no significant changes were observed in 3 beta-HSD expression, P450(17) alpha and P450arom demonstrated stage-specific transcriptional regulation. Steady-state levels of P450(17) alpha mRNA were similar during diestrus and early pregnancy before the onset of eCG secretion but increased significantly after the onset of eCG secretion. Cytochrome P450arom mRNA levels decreased significantly after the onset of eCG secretion. Steady-state levels of P450arom mRNA were highest in luteal tissue collected during pregnancy before the onset of eCG secretion and intermediate during diestrus. Secretion of eCG appears to increase luteal estrogen synthesis by a transcriptional up-regulation of P450(17) alpha expression. These data suggest that availability of aromatizable androgens may be rate-limiting in luteal estrogen synthesis before the onset of eCG secretion.
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PMID:Differential transcription of steroidogenic enzymes in the equine primary corpus luteum during diestrus and early pregnancy. 909 61

The oxidative metabolism of delavirdine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is mediated in part by cytochrome P450 3A. The influence of rifabutin, an inducer of certain human cytochrome P450 isozymes, on the steady-state pharmacokinetics of delavirdine was investigated in 12 HIV-positive patients with CD4 counts ranging from 75 to 671/mm3. Both the control group (n = 5) and the rifabutin group (n = 7) received 400 mg delavirdine mesylate every 8 h for 30 days; subjects in the rifabutin group took a 300 mg, once-daily dose of rifabutin on study days 16-30. Harvested plasma from serial blood samples collected after dosing on days 15, 16, and 30 was assayed for delavirdine and its N-desalkyl metabolite concentrations using a reversed-phase HPLC method. Blood samples obtained on days 16 and 30 were also assayed for rifabutin by HPLC. Delavirdine mesylate alone or in combination with rifabutin was well-tolerated. On day 30, statistically significant differences between groups were observed for all delavirdine pharmacokinetic parameters (P < 0.046). After coadministration of rifabutin and delavirdine mesylate for 2 weeks, oral clearance of delavirdine increased five-fold, resulting in lower steady-state plasma delavirdine concentrations. Rifabutin pharmacokinetic parameters were similar to those previously reported. Concomitant use of delavirdine and rifabutin at the recommended dose for each drug is discouraged. Maintaining therapeutic concentrations of delavirdine in patients on both medications may require dose modification.
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PMID:Pharmacokinetic study of the interaction between rifabutin and delavirdine mesylate in HIV-1 infected patients. 922 61

Human pulmonary tissue are known to contain enzymes mediating procarcinogen activation. Peripheral blood lymphocytes and bronchoalveolar macrophages (BAMs) have been used as surrogates for the lung in studies involving cytochrome P450 (CYP) parameters, including CYP1A1 inducibility in relation to susceptibility to lung cancer. In this study, a comprehensive view of the expression patterns of xenobiotic-metabolizing CYP forms in human BAMs and peripheral blood lymphocytes was obtained by using gene-specific reverse transcriptase-polymerase chain reaction analysis. These patterns were compared with that in the whole lung. mRNAs of CYP2B6/7, CYP2C, CYP2E1, CYP2F1, CYP3A5, and CYP4B1 were detected in all seven BAM samples studied; however, only the mRNA of CYP2E1 was found consistently in all eight lymphocyte samples. The amounts of amplification products of CYP2B6/7, CYP2C, CYP3A5, and CYP4B1 were low and inconsistent, indicating low levels of expression in lymphocytes. Consistent with previous knowledge, mRNAs of CYP1A1, CYP2B6/7, CYP2E1, CYP2F1, CYP3A5, and CYP4B1 were detected in whole-lung tissue. These results give an overall picture of the expression of CYP genes in the xenobiotic-metabolizing families CYP1, CYP2, and CYP3 in BAMs, peripheral blood lymphocytes, and whole-lung tissue and will aid in directing future studies on the respective protein products. The differences in the CYP gene expression patterns between lung and lymphocytes cast additional doubt on the use of lymphocytes as a surrogate for the lung.
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PMID:Detection of mRNA encoding xenobiotic-metabolizing cytochrome P450s in human bronchoalveolar macrophages and peripheral blood lymphocytes. 936 12

Long-term tamoxifen therapy is associated with increased risk of uterine endometrial cancer and benign alterations. Tamoxifen is metabolized to reactive intermediates by endometrial tissue, and tamoxifen therapy-induced DNA adducts have been found in human endometrium. Since metabolic activation is often catalyzed by cytochrome P450 (CYP) enzymes, the expression profile of individual xenobiotic-metabolizing CYP genes was studied in human uterine endometrium by reverse transcriptase-polymerase chain reaction. The following CYP mRNAs were detected: CYP2B6, CYP2C, CYP2E1, CYP3A4, CYP3A5, CYP4B1, and CYP11A. Amplification of CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP2F1, CYP3A7, and CYP19 was not found. CYP3A5 and CYP4B1 transcripts were found only in samples from premenopausal women. These data suggest that the human endometrial epithelium has the potential of producing CYP enzymes known to generate genotoxic intermediates from tamoxifen and metabolites that affect oestrogen receptors.
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PMID:Expression of cytochrome P450 genes encoding enzymes active in the metabolism of tamoxifen in human uterine endometrium. 949 38

Saquinavir is an HIV protease inhibitor with no, or limited, effect on the activity of other structurally related human aspartic proteinases. As with other HIV protease inhibitors, saquinavir inhibits the cleavage of the gag-pol protein substrate leading to the release of structurally defective and functionally inactive viral particles. It is active on both HIV-1 and HIV-2, and also has activity on chronically infected cells and HIV strains resistant to reverse transcriptase inhibitors. Synergy of action has been observed with other antiretroviral drugs. Saquinavir is characterised by a low bioavailability which is further reduced in the fasting state. Metabolism is mainly hepatic through cytochrome P450 (CYP) 3A4, but intestinal metabolism through the same system has also been reported. To achieve higher drug plasma concentrations and increase the antiviral effect, a new formulation of saquinavir with a higher bioavailability has recently been introduced. Higher plasma drug concentrations may also be obtained by combining the drug with CYP blockers, such as ritonavir or ketoconazole. Because of its metabolic interference with the CYP system, saquinavir cannot be coadministered with astemizole, terfenadine or cisapride. Rifampicin (rifampin) is also contraindicated because coadministration can lead to decreases in saquinavir concentrations. Interactions have also been reported with other drugs metabolised through the same system, including non-nucleoside reverse transcriptase inhibitors and HIV protease inhibitors. Resistance has been observed after both in vitro and in vivo drug exposure, with a relatively specific mutation profile compared with other protease inhibitors. Saquinavir is generally well tolerated, with mild gastrointestinal symptoms representing the most commonly observed adverse effects. Although characterized by low bioavailability, in phase III trials saquinavir has been shown to have clinical efficacy in terms of survival and progression rate. As with the other protease inhibitors, saquinavir should be used in combination with other antiretroviral drugs. Current therapeutic guidelines, however, recommend the selection of an initial treatment regimen with other protease inhibitors with higher in vivo activity in terms of RNA and CD4 response. The results of ongoing studies will clarify to what extent a new saquinavir formulation, recently introduced, is superior to the previous one in terms of antiviral activity and to provide comparisons with other protease inhibitors. Further studies are also needed to define the best place of saquinavir within treatment strategies based on protease inhibitors, particularly in respect to the optimal sequence for its use with other protease inhibitors, and the dynamics of cross-resistance and its role within regimens based on the combination of protease inhibitors.
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PMID:Saquinavir. Clinical pharmacology and efficacy. 953 81

We developed a quantitative competitive reverse transcriptase-polymerase chain reaction (QC RT-PCR) assay to measure mRNA levels of seven human cytochrome P450 (P450, CYP) genes and microsomal epoxide hydrolase (EH) simultaneously. This assay employs an exogenous recombinant RNA (rcRNA) molecule as an internal standard that shares PCR primer and hybridization probe sequences with CYP1A1, CYP1A2, CYP2A6/7, CYP2D6, CYP2E1, CYP2F1, CYP3A4/5/7, and EH mRNA. Because each rcRNA molecule contains several primer sequences, an entire battery of genes that exhibit differential responsiveness to various classes of xenobiotics may be measured simultaneously from one population of cDNA molecules. In this study, we demonstrated the precision and power of the assay using small amounts of human liver total RNA. We also report for the first time quantitative profiles of P450 and EH mRNA abundance in eight human livers. Cytochrome P450 2E1 mRNA maintained the highest abundance (average 6.67 x 10(7) molecules/microg of total RNA) and least variation (13 fold) in all livers examined. Cytochrome P450 1A2, CYP2A6/7, CYP2D6, CYP3A4/5, and EH mRNAs were approximately one order of magnitude less abundant than CYP2E1 transcripts, with CYP2D6 levels exhibiting the greatest variation (220 fold) between individuals. This QC RT-PCR assay should prove valuable for measuring basal and induced mRNAs in different cell types in vitro, as well as in biomonitoring applications where individuals are exposed or hypersusceptible to certain xenobiotic-initiated toxicities.
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PMID:Quantification of multiple human cytochrome P450 mRNA molecules using competitive reverse transcriptase-PCR. 953 3

CYP1B1 and CYP1A1 expression and metabolism of 7,12-dimethylbenz(a)anthracene (DMBA) have been characterized in early-passage human mammary epithelial cells (HMECs) isolated from reduction mammoplasty tissue of seven individual donors. The level of constitutive microsomal CYP1B1 protein expression was donor dependent (<0.01-1.4 pmol/mg microsomal protein). CYP1B1 expression was substantially induced by exposure of the cells to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to levels ranging from 2.3 to 16.6 pmol/mg among the seven donors. Extremely low, reproducible levels of constitutive CYP1A1 expression were detectable in three donors (0.03-0.16 pmol/mg microsomal protein). TCDD inductions were larger for CYP1A1, as compared to CYP1B1, demonstrating substantial variability in the induced levels among the donors (0.8-16.5 pmol/mg). Northern and reverse transcriptase PCR analyses corroborate the donor-dependent differences in protein expression, whereby CYP1B1 mRNA (5.2 kb) was constitutively expressed and was highly induced by TCDD (33-fold). The contributions of CYP1B1 and CYP1A1 to the metabolism of DMBA were analyzed using recombinant human CYP1B1 and CYP1A1, as references, in conjunction with antibody-specific inhibition analyses (anti-CYP1B1 and anti-CYP1A1). Constitutive microsomal activity exhibited a profile of regioselective DMBA metabolism that was characteristic of human CYP1B1 (increased proportions of 5,6- and 10,11-DMBA-dihydrodiols), which was inhibited by anti-CYP1B1 (84%) but not by anti-CYP1A1. TCDD-induced HMEC microsomal DMBA metabolism generated the 8,9-dihydrodiol of DMBA as the predominant metabolite, with a regioselectivity similar to that of recombinant human CYP1A1, which was subsequently inhibited by anti-CYP1A1 (79%). A CYP1B1 contribution was indicated by the regioselectivity of residual metabolism and by anti-CYP1B1 inhibition (25%). DMBA metabolism analyses of one of three donors expressing measurable basal expression of CYP1A1 confirmed DMBA metabolism levels equivalent to that from CYP1B1. The HMECs of all donors expressed similar, very high levels of the aryl hydrocarbon receptor and the aryl hydrocarbon nuclear translocator protein, suggesting that aryl hydrocarbon receptor and aryl hydrocarbon nuclear translocator protein expression are not responsible for differences in cytochrome P450 expression. This study indicates that CYP1B1 is an important activator of polycyclic aromatic hydrocarbons in the mammary gland when environmental chemical exposures minimally induce CYP1A1. Additionally, certain individuals express low levels of basal CYP1A1 in HMECs, representing a potential risk factor of mammary carcinogenesis through enhanced polycyclic aromatic hydrocarbon bioactivation.
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PMID:Characterization of CYP1B1 and CYP1A1 expression in human mammary epithelial cells: role of the aryl hydrocarbon receptor in polycyclic aromatic hydrocarbon metabolism. 962 76

Complementary DNA fragments encoding cynomolgus monkey CYP1A2 were amplified by the reverse transcriptase-polymerase chain reaction (RT-PCR) method from the liver total RNA of a 3-methylcholanthrene (3-MC)-treated cynomolgus monkey. The nucleotide sequence determined was 1630 bp long and contained an open reading frame for a polypeptide of 516 residues. The nucleotide and the deduced amino acid sequences of cynomolgus monkey CYP1A2 showed 95.1 and 92.8% identities to those of human CYP1A2, respectively. The level of CYP1A2 mRNA in the liver of untreated cynomolgus monkey was very low. Treatment with 3-MC increased it. Still, it was one-fortieth that of CYP1A1. Cynomolgus monkey CYP1A2 expressed in recombinant yeasts activated 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,8dimethylimidazo[4,5-flquinoxaline (MeIQx) at efficient rates in the umu mutagenicity test. This cytochrome P450 (CYP) also activated 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), but less efficiently. These results indicate that cynomolgus monkeys have a functionally active CYPIA2 gene, but its expression level is very low in the liver of untreated cynomolgus monkeys.
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PMID:Molecular cloning and functional analysis of cynomolgus monkey CYP1A2. 969 97

Atevirdine mesylate (U-87201E) is a highly specific nonnucleoside inhibitor of human immunodeficiency virus type 1 reverse transcriptase. The absorption, metabolism, and excretion of atevirdine were investigated in male and female Sprague-Dawley rats after oral administration of nonradiolabeled atevirdine mesylate at doses of 20 mg/kg/day or 200 mg/kg/day for 8 days, with [14C]atevirdine mesylate single doses of 10 mg/kg or 100 mg/kg on study days 1 and 10. The distribution of [14C]atevirdine mesylate was also evaluated by whole-body autoradiography in male and female Sprague-Dawley, pregnant Sprague-Dawley, and male Long-Evans rats after a single 10 mg/kg oral dose. Plasma levels of atevirdine and its N-desethyl and O-desmethyl metabolites were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection, urine and feces were profiled for atevirdine and metabolites by HPLC with radiochemical detection, major metabolites in urine were isolated and identified by nuclear magnetic resonance and mass spectrometry, and minor urinary metabolites were identified by liquid chromatography/mass spectrometry. Atevirdine was rapidly absorbed. The pharmacokinetics of atevirdine were nonlinear. Gender differences in the pharmacokinetics and metabolism of atevirdine were observed, consistent with the involvement of cytochrome P450 3A. Atevirdine effectively crossed the blood-brain barrier and had a high rate of maternal-fetal transfer. At the low doses, <2% of the dose was excreted as unchanged parent drug, while atevirdine constituted 9%-25% of the dose at the high doses. The metabolism of atevirdine was extensive in the rat and involved N-deethylation, O-demethylation, hydroxylation at the C-6 position of the indole ring, and hydroxylation of the pyridine ring.
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PMID:Absorption, distribution, metabolism, and excretion of atevirdine in the rat. 976 7

In this study, cytochrome P450 (CYP; EC 1.14.14.1)-dependent activities and P450 isoenzyme patterns were determined in human monocytes and macrophages, which play a major role in antigen processing including small molecular weight compounds which cause contact dermatitis or drug-allergic reactions. Using reverse transcriptase-polymerase chain reaction (RT-PCR) we determined the mRNA expression of eight CYPs (1A1, 1A2, 1B1, 2B6/7, 2E1, 3A3/4, 3A7 and 4B1) in human blood monocytes and macrophage subsets 27E10 and RM3/1. To study the influence of known P450 inducers, monocytes were incubated in vitro with ethanol, dexamethasone, cyclosporin A (CSA), benzanthracene (BA), phenobarbital (PB), lipopolysaccharide (LPS) and 12-O-tetradecanoyl-phorbol-13-acetat (TPA) for 24 hr. Percoll density gradient isolated monocytes as well as the pro-inflammatory macrophage subtype 27E10 expressed 1B1, 2E1 and 2B6/7. On the other hand, in the anti-inflammatory macrophage subtype RM3/1, predominantly 1B1 and to some extent 2B6/7 were found. Treatment with cyclosporin A, phenobarbital, benzanthracene or ethanol resulted in induction of the expression of 3A3/4. CYP1B1 was the predominant isoenzyme in all monocytes and macrophages. In monocytes purified by adherence or induced by benzanthracene, lipopolysaccharide or 12-O-tetradecanoyl-phorbol-13-acetat, 1A1 was also expressed. Northern blot analysis confirmed the presence of CYP1B1 in monocytes and macrophages, a presence which was also demonstrated on the protein level by immunoblot and by immunohistochemical staining of the cells. The expression of several CYPs in monocytes/macrophages suggests that these cells may be important in the metabolism of small molecular weight compounds, which play a role in allergic contact dermatitis and drug reactions. Of particular interest is the remarkably strong expression of the recently identified dioxin inducible CYP1B1, known to be present in a wide range of malignant tumors.
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PMID:Cytochrome P450 1B1: a major P450 isoenzyme in human blood monocytes and macrophage subsets. 980 19


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