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)

Human first-trimester placentas were screened for the expression of xenobiotic-metabolizing cytochrome P450 (CYP) genes. mRNAs of CYP1A1, CYP1A2, CYP2C, CYP2D6, CYP2E1, CYP2F1, CYP3A4, CYP3A5, CYP3A7, and CYP4B1 were identified by reverse transcriptase-polymearse chain reaction (RT-PCR) in at least some of the six placental samples studied. CYP2A and CYP2B message were absent in all samples. The level of all of these CYP mRNAs was lower compared to the corresponding levels in liver or lung. the catalytic activity marker (7-ethoxyresorufin O-deethylase) was inducible in the placentas by maternal cigarette smoking. Thus, the regulatory system of placental CYP1A1, mediated by the Ah-receptor, appears to be developed as early as the first trimester of pregnancy. Three immunoreactive bands from placental microsomes were detected by an antihuman CYP3A4 antibody, but no functional activity of CYP3A enzymes could be detected. These results show that placental tissue during the first trimester of pregnancy has the potential of expressing several CYP genes, and forms a basis for subsequent analysis of these forms at the protein and functional level.
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PMID:Detection of cytochrome P450 gene expression in human placenta in first trimester of pregnancy. 869 64

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

The cytochromes P450 are a large family of haemoproteins which have a major role in the oxidative metabolism of a wide range of xenobiotics and some endogenous compounds. In this study the presence of individual members of the CYP1, CYP2 and CYP3 P450 families has been investigated by reverse transcriptase polymerase chain reaction in different regions of normal human brain consisting of frontal and temporal cortices, mid brain, cerebellum, pons and medulla. All the P450s were identified in specific regions of brain with CYP1A1 and CYP2C being the most frequently expressed forms of P450. Sequencing identified the CYP2C PCR product as CYP2C8. This study indicates that individual P450 mRNAs are present in human brain and are found in specific brain regions. The distribution of individual P450s in different regions of human brain is likely to be highly important in determining the response of the brain to toxic foreign compounds.
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PMID:Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain. 958 55

The capacity of three clinically available nonnucleoside reverse transcriptase inhibitors (NNRTIs) to inhibit the activity of human cytochromes P450 (CYPs) was studied in vitro using human liver microsomes. Delavirdine, nevirapine, and efavirenz produced negligible inhibition of phenacetin O-deethylation (CYP1A2) or dextromethorphan O-demethylation (CYP2D6). Nevirapine did not inhibit hydroxylation of tolbutamide (CYP2C9) or S-mephenytoin (CYP2C19), but these CYP isoforms were importantly inhibited by delavirdine and efavirenz. This indicates the likelihood of significantly impaired clearance of CYP2C substrate drugs (such as phenytoin, tolbutamide, and warfarin) upon initial exposure to these two NNRTIs. Delavirdine and efavirenz (but not nevirapine) also were strong inhibitors of CYP3A, consistent with clinical hazards of initial cotreatment with either of these drugs and substrates of CYP3A. The in vitro microsomal model provides relevant predictive data on probable drug interactions with NNRTIs when the mechanism is inhibition of CYP-mediated drug biotransformation. However, the model does not incorporate interactions attributable to enzyme induction.
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PMID:Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. 1122 65

Environmental chemicals are one of the risk factors in breast cancer genesis. Cytochrome P450 (CYP) enzymes play a major role in the activation of these chemicals. Using highly specific and sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. the expression profile of all major xenobiotic metabolizing CYP forms was screened in breast tumour and surrounding tumour free (control) breast tissue in a series of 20 sample pairs obtained from females with infiltrating ductal carcinoma. The levels of CYPIAI mRNA were very low in both tumour and normal tissue. CYP1B1, CYP2B6, CYP2C, CYP2D6, CYP2E1, CYP4B1, and CYP11A1 expressions were positive in both tumours and control tissue. CYP2A6, CYP2A7, CYP2A13, CYP2F1, CYP3A4, CYP3A5. and CYP3A7 mRNAs were expressed neither in tumours nor in control tissue. These results show that several CYPs. responsible for the activation of a quite large number of procarcinogens and genotoxic estrogen metabolites. are expressed in breast tissue with a lack of qualitative differences in CYP expression at mRNA level between breast tumours and surrounding normal breast.
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PMID:The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue. 1176 4

Besides hepatic P450 (cytochrome P450) metabolism, there is increasing interest in the possibility of intratumoral activation of oxazaphosphorines by P450. Therefore, we investigated the expression of P450 (CYP2C8, CYP2C9, CYP2C18, and CYP2C19) by RT (reverse transcriptase)-polymerase chain reaction (PCR) and of CYP2C9 by Western blotting in 10 different breast tumor samples. Since P450 may be down regulated by interleukin (IL) IL-6, the receptor (R) for IL-6 was analyzed by RT-PCR and IL-6 in supernatants was calculated from ELISA data. None of the breast tumors was positive for CYP2C18 and CYP2C19 mRNA, whereas CYP2C8 and CYP2C9 were detected in all 10 breast tumors. Correspondingly, all breast tumors tested (9 of 10) revealed low, but nevertheless positive, staining of the CYP2C9 protein. All 10 samples were positive for the IL-6 receptor mRNA. ELISA measurement of IL-6 cytokine in supernatants revealed that all measured samples (8 of 10) were producing IL-6, the amounts ranging from 0.004 to 3.1 ng/g(tumor tissue). In summary, we have demonstrated that tumors of the breast express two out of four members of the CYP2C family, indicating that activation of such prodrugs as oxazaphosphorines may take place intratumorally. The presence of the IL-6 receptor and of IL-6 cytokine, which is produced in an autocrine manner, opens up the possibility that the well-known down regulating effect of IL-6 also takes place in breast tumors and might explain the weak or even absent expression of different CYP2C members.
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PMID:CYP2C and IL-6 expression in breast cancer. 1475 13

TMC125 is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. TMC125 is an inducer of CYP3A and an inhibitor of CYP2C. This trial evaluated the effect of TMC125 on the pharmacokinetics and pharmacodynamics of methadone. In an open-label, add-on, 1-way interaction trial, 16 male HIV-negative volunteers on stable methadone maintenance therapy received 100 mg TMC125 bid for 14 days. Plasma concentrations and pharmacokinetic parameters of R- and S-methadone isomers were determined on days -1, 7, and 14 and of TMC125 on days 7 and 14. Safety and tolerability were assessed. The LSmeans ratios (90% confidence interval) for AUC(24h), C(max), and C(min) of the pharmacologically active R-methadone were 1.08 (1.02-1.13), 1.03 (0.97-1.09), and 1.12 (1.05-1.19), respectively, on day 7 and 1.06 (0.99-1.13), 1.02 (0.96-1.09), and 1.10 (1.02-1.19), respectively, on day 14 compared with methadone alone. No withdrawal symptoms were observed; dose adjustment of methadone was not required. The concomitant administration of TMC125 and methadone was generally safe and well tolerated. TMC125 has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of methadone. No dose adjustment for methadone is anticipated when coadministered with TMC125.
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PMID:Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers. 1819 53

Etravirine (TMC125) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed for the treatment of HIV-1 infections. The drug was recently approved by the US FDA to be used in combination with other anti-HIV medications. Etravirine is a highly flexible diarylpyrimidine compound, with favorable binding interactions toward mutant HIV strains as well as wild-type virus. This conformation confers an increased genetic barrier to resistance compared with other NNRTIs: multiple mutations are required before there is a decrease in susceptibility to etravirine; whereas, only one mutation (K103N) is typically needed to confer high-level resistance to the first-generation NNRTIs. In vitro, etravirine is predominantly metabolized by cytochrome P450 (CYP)3A4 and CYP2C (2C9, 2C18 and 2C19). In vivo, the most important metabolic pathway for etravirine is methyl hydroxylation, with subsequent glucuronidation of the metabolites. Etravirine is an inducer of CYP3A4 and a weak inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. In Phase II and III trials in treatment-experienced patients, treatment with etravirine led to better virological suppression than placebo. In the DUET I and II trials (Phase III), approximately 60% of the etravirine group achieved a confirmed viral load of less than 50 copies/ml at week 24, compared with approximately 40% in the placebo arm. The mean change in viral load at week 24 was -2.34 (standard deviation: 1.31) and -1.68 (1.40) log(10) copies/ml in the etravirine and placebo groups, respectively. The presence of three or more NNRTI-associated mutations at baseline negatively influenced the outcome. There were no safety concerns and no major differences in frequency or severity of side effects between etravirine and placebo groups, with the exception of rash. Furthermore, the overall rate of discontinuation due to any adverse event was similar between the etravirine and placebo groups. The most common adverse events reported were rash and nausea.
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PMID:Etravirine for the treatment of HIV infection. 1866 9

Etravirine (formerly TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant strains of HIV-1. Etravirine has been approved in several countries for use as part of highly active antiretroviral therapy in treatment-experienced patients. In vivo, etravirine is a substrate for, and weak inducer of, the hepatic cytochrome P450 (CYP) isoenzyme 3A4 and a substrate and weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. An extensive drug-drug interaction programme in HIV-negative subjects has been carried out to assess the potential for pharmacokinetic interactions between etravirine and a variety of non-antiretroviral drugs. Effects of atorvastatin, clarithromycin, methadone, omeprazole, oral contraceptives, paroxetine, ranitidine and sildenafil on the pharmacokinetic disposition of etravirine were of no clinical relevance. Likewise, etravirine had no clinically significant effect on the pharmacokinetics of fluconazole, methadone, oral contraceptives, paroxetine or voriconazole. No clinically relevant interactions are expected between etravirine and azithromycin or ribavirin, therefore, etravirine can be combined with these agents without dose adjustment. Fluconazole and voriconazole increased etravirine exposure 1.9- and 1.4-fold, respectively, in healthy subjects, however, no increase in the incidence of adverse effects was observed in patients receiving etravirine and fluconazole during clinical trials, therefore, etravirine can be combined with these antifungals although caution is advised. Digoxin plasma exposure was slightly increased when co-administered with etravirine. No dose adjustments of digoxin are needed when used in combination with etravirine, however, it is recommended that digoxin levels should be monitored. Caution should be exercised in combining rifabutin with etravirine in the presence of certain boosted HIV protease inhibitors due to the risk of decreased exposure to etravirine. Although adjustments to the dose of clarithromycin are unnecessary for the treatment of most infections, the use of an alternative macrolide (e.g. azithromycin) is recommended for the treatment of Mycobacterium avium complex infection since the overall activity of clarithromycin against this pathogen may be altered when co-administered with etravirine. Dosage adjustments based on clinical response are recommended for clopidogrel, HMG-CoA reductase inhibitors (e.g. atorvastatin) and for phosphodiesterase type-5 inhibitors (e.g. sildenafil) because changes in the exposure of these medications in the presence of co-administered etravirine may occur. When co-administered with etravirine, a dose reduction or alternative to diazepam is recommended. When combining etravirine with warfarin, the international normalized ratio (INR) should be monitored. Systemic dexamethasone should be co-administered with caution, or an alternative to dexamethasone be found as dexamethasone induces CYP3A4. Caution is also warranted when co-administering etravirine with some antiarrhythmics, calcineurin inhibitors (e.g. ciclosporin) and antidepressants (e.g. citalopram). Co-administration of etravirine with some antiepileptics (e.g. carbamazepine and phenytoin), rifampicin (rifampin), rifapentine or preparations containing St John's wort (Hypericum perforatum) is currently not recommended as these are potent inducers of CYP3A and/or CYP2C and may potentially decrease etravirine exposure. Antiepileptics that are less likely to interact based on their known pharmacological properties include gabapentin, lamotrigine, levetiracetam and pregabalin. Overall, pharmacokinetic and clinical data show etravirine to be well tolerated and generally safe when given in combination with non-antiretroviral agents, with minimal clinically significant drug interactions and no need for dosage adjustments of etravirine in any of the cases, or of the non-antiretroviral agent in the majority of cases studied.
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PMID:Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. 2114 66


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