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)

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

Amprenavir is a novel protease inhibitor with antiviral activity, and was approved in the U.S. (AGEN-ERASE) in 1999 for use in combination with other antiretrovirals for the treatment of HIV infection. The drug is developed by Kissei Pharmaceuticals Co., Ltd. in Japan, approved in the same year, and has been distributed by them (PROZEI). Amprenavir achieves a viral load of less than 400 copies/ml when it is given in triple combination therapy in both therapy-naive patients and patients previously treated with nucleoside reverse transcriptase inhibitors (NRTI). The recommended dose of amprenavir is eight 150-mg capsules, twice daily, or 1200 mg, b.i.d. Amprenavir may be taken with or without a meal; however, it should not to be taken with high-fat meals because its oral bioavailability may possibly be affected by fat. One of the major concerns associated with anti-HIV agents is the resistance mutation development, and the presence of I50V, M46I/L, I47V, I54L/V and I84V genotype has been observed in amprenavir therapy experienced subjects. Differences in resistance patterns and resistance mutation interactions may have amprenavir recognized as an alternative choice of drugs in maintaining efficacy. Therefore, amprenavir is believed to add an important treatment option in HIV infection therapy. It should be noted that P450 isozyme CYP3A4 is responsible for amprenavir; thus, care must be taken to avoid combined amprenavir with drugs that affect the action of CYP3A4, that act on the production CYP3A4 substrates, or that are metabolized by CYP3A4 metabolism. Amprenavir is the fifth protease inhibitor approved in Japan, and it is important to understand its differential and identical properties from other protease inhibitors to maximize its efficacy.
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PMID:[Pharmacological study and clinical effect of HIV protease inhibitor amprenavir]. 1123 98

HIV-positive patients may experience erectile dysfunction and Viagra may be prescribed as a treatment. Viagra is processed by the P450 enzyme system and may negatively interact with other drugs, including protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTI). Protease inhibitors and delavirdine may increase Viagra levels and increase the risk of side effects. The NNRTIs efavirenz and nevirapine may lower levels of Viagra and reduce its effectiveness. The combination of Viagra with amyl nitrate can cause life-threatening drops in blood pressure.
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PMID:A note about Viagra. 1136 23

Phenobarbital (PB) induces various gene encoding drug/steroid-metabolizing enzymes such as cytochromes P450 (P450s) and transferases. Although the nuclear orphan constitutive active receptor (CAR) has been identified as a key transcription factor that regulates the induction of CYP2B, the full scope of CAR-regulated genes still remains a major question. To this end, reverse transcriptase-polymerase chain reaction and cDNA microarray techniques were employed to examine gene expression in wild-type and CAR-null mice. The results show that a total of 138 genes were detected to be either induced or repressed in response to PB treatment, of which about half were under CAR regulation. Including CYP2B10, CYP3A11, and NADPH-CYP reductase, CAR regulated a group of the PB-induced drug/steroid-metabolizing enzymes. Enzymes such as amino levulinate synthase 1 and squalene epoxidase displayed CAR-independent induction by PB. Cyp4a10 and Cyp4a14 represented the group of genes induced by PB only in CAR-null mice, indicating that CAR may be a transcription blocker that prevents these genes from being induced by PB. Additionally, the group of genes encoding enzymes and proteins involved in basic biological processes such as energy metabolism underwent the CAR-dependent repression by PB. Thus, CAR seems to have diverse roles, both as a positive and negative regulator, in the regulation of hepatic genes in response to PB beyond drug/steroid metabolism.
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PMID:Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. 1175 99

The present work aims to determine the relevance of an astrocytoma cell line U373 MG, for assessing the role of some astroglial cytochrome P450 in neurotoxicity and neuroprotection. CYP1B1, CYP2C8, CYP2C9, CYP2D6, CYP2J2, CYP2E1 and CYP4A11 mRNA were detected by reverse transcriptase-polymerase chain reaction in control U373 MG cell cultures. Among them we focused on CYP1B1 expression. After 48 h treatment with a range of concentrations of interleukin-1beta (1, 5, 10 ng/ml) used to simulate stress conditions, CYP1B1 mRNA expression was enhanced in a dose-dependent way. This increased expression was followed 24 h later by an increase in protein level, determined by Western-blot. N-acetylcysteine (NAC) partially inhibited this effect both on the mRNA and protein levels. As CYP1B1 activates procarcinogenic compounds to reactive metabolites, an increase in this P450 isoform will participate to toxic consequences of an inflammatory/oxidative stress. NAC will prevent this deleterious effect.
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PMID:Astroglial CYP1B1 up-regulation in inflammatory/oxidative toxic conditions: IL-1beta effect and protection by N-acetylcysteine. 1256 1

P450 aromatase catalyzes the conversion of androgens to estrogens and plays a key role in the cell growth of hormone-dependent breast cancer in postmenopausal women. On the other hand, matrix metalloproteinases (MMPs), which can degrade almost all components of the extracellular matrix, play a crucial role in tumor cell invasion and cancer metastasis. In the present study the effect of letrozole on cell proliferation of estrogen receptor (ER)-positive MCF-7 human epithelial breast cancer and MCF-12A human mammary epithelial cells was studied. The effect of letrozole on the in vitro release of MMPs, particularly type IV collagenases (MMP-2 and MMP-9), by the ER-positive MCF-7 cells was also investigated, using a solid-phase method of high sensitivity and accuracy. Using RNA isolates from cell lines MCF-7 and MCF-12A, reverse transcriptase-polymerase chain reaction analysis revealed that only MCF-7 cells express the P450 aromatase gene. Study of the effects of letrozole alone and the hormones 17-beta-estradiol, testosterone and 4-androstene-3, 17-dione in the presence and absence of letrozole on cell growth at the DNA synthesis level showed that letrozole significantly suppressed the endogenous aromatase-induced proliferation of MCF-7 cells. The majority of MMPs secreted by MCF-7 cells were identified in their pro-forms, which was in accordance with the low metastatic potential determined for these cells. After treatment of cells with letrozole (10 nM) for 24 and 48 h, significant inhibition of MMP levels was obtained. Furthermore, concurrent treatment of MCF-7 cells with 17-beta-estradiol in the presence of letrozole significantly suppressed the estradiol-induced stimulation of MMP levels. The data obtained suggest that letrozole is a potent in vitro inhibitor of cell proliferation and of type IV collagenases expressed by ER-positive MCF-7 cells and may be of value for suppressing breast tumor growth and invasiveness.
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PMID:Letrozole as a potent inhibitor of cell proliferation and expression of metalloproteinases (MMP-2 and MMP-9) by human epithelial breast cancer cells. 1256 69

In trout and mammals, the major extrahepatic expression site for CYP3A forms is in the intestine. A cDNA encoding a new CYP3A subfamily member was isolated from rainbow trout intestinal ceca by reverse transcriptase-polymerase chain reaction (RT-PCR), followed by rapid amplification of cDNA ends (RACE)-PCR. In a set of two primers for PCR, a consensus sequence in the highly conserved regions in 17 CYP3A sequences was used for one primer, and the second primer was designed based on adapter sequence ligated on the 5(') and 3(') cDNA ends. The 3(') and 5(') end nucleotide sequences of RACE-PCR products were used for the priming sites for the full-length cDNA in RT-PCR. The resulting 2615-bp cDNA contained an open reading frame of 1554 bp encoding a 518-amino acid residue protein (M(r)=59057.13, pI=6.15) with 26 amino acid differences from that of the previously cloned rainbow trout CYP3A27. The cDNA was assigned as CYP3A45 by the P450 Nomenclature Committee. The deduced amino acid sequence of rainbow trout CYP3A45 was 94% identical with trout CYP3A27, 72% with killifish CYP3A56, and 71% with both medaka CYP3A40 and killifish CYP3A30 in positional alignment comparisons. Northern blotting by a CYP3A45-specific nucleotide probe showed that the major expression site was the intestinal ceca rather than the liver in both male and female trout. Recombinant baculovirus containing a CYP3A45 cDNA (Bv-3A45) was constructed under polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus and used to express CYP3A45 protein in Spodoptera frugiperda cells. The Western blot showed that the expressed CYP3A45 protein comigrated with purified LMC5 P450 and was recognized by anti-LMC5 polyclonal antibodies. The expressed CYP3A45 showed catalytic activities for the 6 beta-, 2 beta-, and 16 beta-hydroxytestosterones of 1.76, 0.193, and 0.078 nmol/min/nmol CYP3A45, respectively. In summary, a second form of CYP3A with steroid hydroxylase activity, CYP3A45, has been cloned from rainbow trout and the major site of expression was in the intestinal tissues.
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PMID:Cloning, tissue distribution, and functional studies of a new cytochrome P450 3A subfamily member, CYP3A45, from rainbow trout (Oncorhynchus mykiss) intestinal ceca. 1264 70

Estrogens are key regulators of sexual differentiation and development in vertebrates. The P450 aromatase (P450arom) is the steroidogenic enzyme responsible for the synthesis of estrogens from androgens. In the adult rat testis, aromatase transcripts and activity have been observed in somatic cells and germ cells, including pachytene spermatocytes (PS) and round spermatids (RS), but little is known concerning regulation of the aromatase gene expression, especially in germ cells. The quality of germ cell preparations was assessed by the absence of androgen-binding protein and stem cell factor transcripts, two specific markers for Sertoli cells. By employing a competitive quantitative reverse transcriptase-polymerase chain reaction technique, we confirmed that germ cells contained P450arom transcripts and demonstrated that the aromatase gene was up-regulated by cAMP. Conversely, transforming growth factor (TGF) beta1 inhibited Cyp19 gene expression in a dose- and a time-dependent manner in both PS and RS. The addition of tumor necrosis factor (TNF) alpha to purified germ cells induced an increase of the amount of P450arom mRNA in PS, although an inhibitory effect was observed in RS. When PS were treated with dexamethasone (Dex), a similar enhancement of the aromatase transcript level was observed, whereas an inhibitory effect was recorded for RS. Furthermore, in either TGFbeta1- or TNFalpha-treated germ cells, the addition of Dex stimulated the aromatase gene transcription. Experiments using 5' rapid amplification of cDNA ends suggested that promoter PII is mainly concerned in the regulation of the aromatase gene expression in germ cells of adult male rats; however, the presence of other promoters could not be excluded.
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PMID:Regulation of aromatase gene expression in purified germ cells of adult male rats: effects of transforming growth factor beta, tumor necrosis factor alpha, and cyclic adenosine 3',5'-monosphosphate. 1270 Jan 95

This study is the first systematic investigation of the gestational age-dependent and adult tissue-specific expression patterns of each known mouse CYP family (40 genes) using normalized cDNA panels and uniform reverse transcriptase polymerase chain reaction-based assays. Twenty-seven of the P450s were constitutively expressed during development. The number gradually increased through the phases of gastrulation E7 (n=14), neural patterning and somitogenesis E11 (n=17), organogenesis E15 (n=20), and fetal period E17 (n=21). Cyp2s1, Cyp8a1, Cyp20, Cyp21a1, Cyp26a1, Cyp46, and Cyp51 were detected in each of the four stages studied. Members of family CYP1 demonstrated complex, nonoverlapping embryonic patterns of expression, indicating that Cyp1a1 and Cyp1a2 may not compensate for Cyp1b1 deficiency associated with abnormal eye development. Multiple Cyp forms were found to be constitutively expressed in each of the adult tissues studied: liver (n=31), kidney (n=30), testis (n=26), lung (n=24), and heart (n=13). The tissue-specific P450-expression profiles reported in this study provide a reference for more focused analysis of the tissue-specific and developmental functions of the cytochrome P450 monooxygenases.
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PMID:Comparative expression profiling of 40 mouse cytochrome P450 genes in embryonic and adult tissues. 1274 59

One of seven poor metabolizers of coumarin found in Thai subjects was previously genotyped as heterozygote for the CYP2A6*4 (whole deletion) and CYP2A6*9. Thus, we aimed to investigate the relationship between the genetic polymorphism in the TATA box of the CYP2A6 gene (CYP2A6*9), expression levels of CYP2A6 mRNA and coumarin 7-hydroxylase activities in human livers. Levels of CYP2A6 mRNA were quantified by real-time quantitative reverse transcriptase-polymerase chain reaction. The mean expression levels of CYP2A6 mRNA in individuals with CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 58%, 71% and 21% of the individuals genotyped as CYP2A6*1/*1, respectively. The mean in-vitro coumarin 7-hydroxylase activities in subjects carrying CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 41%, 71% and 12%, respectively, compared to those of the subjects judged as wild-type. Vmax values for coumarin 7-hydroxylation in the liver microsomes from human subjects with genotypes of CYP2A6*1/*1, CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 0.58, 0.26, 0.44 and 0.13 nmol/min/nmol total P450, respectively. CYP2A6 protein levels in human liver microsomes with the CYP2A6*4 and the CYP2A6*9 alleles were markedly decreased. These results suggest that the genetic polymorphism in the promoter region of the CYP2A6 gene (CYP2A6*9) reduced the expression levels of CYP2A6 mRNA and protein in human livers, resulting in the decrease of coumarin 7-hydroxylase activities. Individuals judged as CYP2A6*4/*9 were expected to be poor metabolizers, having extremely low activity of CYP2A6.
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PMID:Decreased coumarin 7-hydroxylase activities and CYP2A6 expression levels in humans caused by genetic polymorphism in CYP2A6 promoter region (CYP2A6*9). 1458 82


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