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)

Deletions and other genome rearrangements are associated with carcinogenesis and inheritable diseases. The pink-eyed unstable (pun) mutation in the mouse is caused by duplication of a 70-kb internal fragment of the p gene. Spontaneous reversion events in homozygous pun/pun mice occur through deletion of a duplicated sequence. Reversion events in premelanocytes in the mouse embryo detected as black spots on the gray fur of the offspring were inducible by the carcinogen x-rays, ethyl methanesulfonate, methyl methanesulfonate, ethyl nitrosourea, benzo[a]pyrene, trichloroethylene, benzene, and sodium arsenate. The latter three carcinogens are not detectable with several in vitro or in vivo mutagenesis assays. We studied the molecular mechanism of the carcinogen-induced reversion events by cDNA analysis using reverse transcriptase-PCR method and identified the induced reversion events as deletions. DNA deletion assays may be sensitive indicators for carcinogen exposure.
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PMID:Carcinogens induce reversion of the mouse pink-eyed unstable mutation. 911 32

MDR1 P-glycoprotein (Pgp 170), a member of the adenosine triphosphate (ATP) binding cassette transporters, acts as an efflux pump for various hydrophobic agents, particularly for xenobiotics such as benzo(a)pyrene. It has also been shown to regulate cell-volume activated chloride channels. Pgp 170 could, therefore, be of particular importance in cellular mechanisms of defence in the airways and in the control of mucus layer composition. For these reasons, we evaluated the precise localization of Pgp 170 in human adult airways. Fresh non-neoplastic bronchial specimens were collected from 33 patients (26 smokers, four exsmokers and three nonsmokers) who underwent surgery for lung carcinoma. The presence of MDR1 messenger ribonucleic acid (mRNA) was demonstrated by reverse transcriptase chain reaction (RT-PCR) in bronchial epithelial cells collected by gentle scraping from either smokers, exsmokers or nonsmokers. Immunodetection of Pgp 170 using a panel of monoclonal antibodies (MRK16, JSB1, C219, C494) was performed either on cryostat or paraffin-embedded sections of histologically normal bronchial tissue. Pgp 170 was constantly detected with intense labelling at the apical surface of ciliated epithelial cells from the surface epithelium or ciliated collecting ducts, and on apical and lateral surfaces of serous cells from bronchial glands. No staining of mucus-secreting cells was observed. Pgp 170 was also demonstrated at the luminal surface of endothelial cells of bronchial capillaries. In conclusion, the expression of MDR1 P-glycoprotein in bronchial structures, particularly at the epithelial apical surface, suggests important roles for this transmembrane protein in human airways.
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PMID:MDR1-Pgp 170 expression in human bronchus. 927 28

Human UDP-glucuronosyltransferases (UGTs) are expressed in a tissue-specific fashion in hepatic and extrahepatic tissues [Strassburg, Manns and Tukey (1998) J. Biol. Chem. 273, 8719-8726]. Previous work suggests that these enzymes play a protective role in chemical carcinogenesis [Strassburg, Manns and Tukey (1997) Cancer Res. 57, 2979-2985]. In this study, UGT1 and UGT2 gene expression was investigated in human oesophageal epithelium and squamous-cell carcinoma in addition to the characterization of individual UGT isoforms using recombinant protein. UGT mRNA expression was characterized by duplex reverse transcriptase-PCR analysis and revealed the expression of UGT1A7, UGT1A8, UGT1A9 and UGT1A10 mRNAs. UGT1A1, UGT1A3, UGT1A4, UGT1A5 and UGT1A6 transcripts were not detected. UGT2 expression included UGT2B7, UGT2B10 and UGT2B15, but UGT2B4 mRNA was absent. UGT2 mRNA was present at significantly lower levels than UGT1 transcripts. This observation was in agreement with the analysis of catalytic activities in oesophageal microsomal protein, which was characterized by high glucuronidation rates for phenolic xenobiotics, all of which are classical UGT1 substrates. Whereas UGT1A9 was not regulated, differential regulation of UGT1A7 and UGT1A10 mRNA was observed between normal oesophageal epithelium and squamous-cell carcinoma. Expression and analysis in vitro of recombinant UGT1A7, UGT1A9, UGT1A10, UGT2B7 and UGT2B15 demonstrated that UGT1A7, UGT1A9 and UGT1A10 catalysed the glucuronidation of 7-hydroxybenzo(alpha)pyrene, as well as other environmental carcinogens, such as 2-hydroxyamino-1-methyl-6-phenylimidazo-(4, 5-beta)-pyridine. Although UGT1A9 was not regulated in the carcinoma tissue, the five-fold reduction in 7-hydroxybenzo(alpha)pyrene glucuronidation could be attributed to regulation of UGT1A7 and UGT1A10. These data elucidate an individual regulation of human UGT1A and UGT2B genes in human oesophagus and provide evidence for specific catalytic activities of individual human UGT isoforms towards environmental carcinogens that have been implicated in cellular carcinogenesis.
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PMID:Regulation and function of family 1 and family 2 UDP-glucuronosyltransferase genes (UGT1A, UGT2B) in human oesophagus. 1002 27

The potent carcinogenicity of dibenzo[a,l]pyrene (DB[a,l]P) in mouse skin is associated with an inflammatory response and a striking epidermal hyperplasia. The mechanism of these tissue responses is not known. However, a recent study has shown DB[a,l]P to be a contact sensitizer. In view of the programmed expression of cytokines during induction of contact hypersensitivity (CHS) and elicitation of CHS reactions, we analyzed cytokine mRNAs in treated skin and draining lymph nodes of SENCAR mice, at selected times after a single, epicutaneous application of DB[a,l]P or dimethylbenz[a]anthracene (DMBA), a substantially weaker carcinogen and a weaker contact sensitizer than DB[a,l]P. Cytokine mRNAs were quantified by first-strand DNA synthesis with reverse transcriptase (RT) and DNA amplification by the polymerase chain reaction (PCR). Histopathology of treated skin was determined in the same experiments. Time-response profiles of interferon (IFN) gamma and interleukin (IL) 2 in the DLN and IL1beta, IL10, tumor necrosis factor (TNF) alpha, and IL4 mRNAs in the skin of mice treated with 200 nmol of DB[a,l]P were in remarkable agreement with established profiles in mice treated with conventional contact sensitizers, e.g., oxazolone or dinitrochlorobenzene. Strong upregulation of DLN IFNgamma mRNA coupled with little change in IL 2 mRNA suggested a CD8(+) T-cell response characteristic of CHS induction. Coordinate expression of epidermal IL1beta, TNFalpha, and IL10 mRNAs, 24 h after DB[a,l]P treatment, was also characteristic of CHS induction. IL1beta and IL10 are upregulated by allergens and not by chemical irritants. Time-response profiles of epidermal IL1beta, TNFalpha, IL10, and IL4 mRNAs, 3-14 d after DB[a,l]P treatment, corresponded with expression of these cytokines during elicitation of CHS reactions. Epidermal IL4 is specifically upregulated during CHS reactions. Cytokine mRNA responses were dose-dependent (50, 100, and 200 nmol of DB[a,l]P) and markedly weaker in animals treated with 400 nmol of DMBA. Significantly, the intensity of epidermal hyperplasia correlated with the strength of the cytokine mRNA signals in DLN and skin. In conclusion, our data support carcinogen-specific CHS as a mechanism by which the very potent carcinogen DB[a,l]P induces epidermal hyperplasia, a requirement for tumor promotion in mouse skin.
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PMID:Profiles of cytokine mRNAs in the skin and lymph nodes of SENCAR mice treated epicutaneously with dibenzo[a,l]pyrene or dimethylbenz[a]anthracene reveal a direct correlation between carcinogen-induced contact hypersensitivity and epidermal hyperplasia. 1065 5

Quercetin is one of the most abundant of the naturally occurring flavonoids. It has been estimated that about 25-50 mg of quercetin are consumed from the daily diet. The chemopreventive effect of quercetin on dietary carcinogen has been intensely studied in animal models; however, knowledge regarding the molecular mechanism is still limited. In this study, the human hepatoma Hep G2 cell line was used to investigate how quercetin prevents benzo[a]pyrene (B[a]P)-induced DNA adducts. The Hep G2 cells were treated with 10 microM B[a]P for 18 hours in the presence or absence of quercetin. The DNA adduct levels, evaluated by 32P postlabeling, decreased in a dose-dependent manner after treatment with quercetin. Cytochrome P-450 1A1 (CYP1A1) and glutathione S-transferase involvement have been well demonstrated in the modulation of B[a]P-induced DNA damage. From the assays of both enzyme activities, quercetin inhibits CYP1A1-linked ethoxyresorufin O-dealkylase activity more effectively than glutathione S-transferase activity. To elucidate the molecular mechanisms, reverse transcriptase-polymerase chain reaction and Western blot were used to evaluate whether the decrease in CYP1A1 enzyme activity by quercetin is mediated because of alterations of CYP1A1 transcription or mRNA stability. The results indicated that quercetin significantly inhibits B[a]P-induced CYP1A1 mRNA and protein expression. From these findings, we conclude that quercetin suppresses B[a]P-induced DNA damage in human Hep G2 cells by altering CYP1A1 gene expression. Thus we suggest that dietary quercetin may have a long-term preventive effect on chemical carcinogenesis, especially in people who eat a diet rich in fruits and vegetables.
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PMID:Quercetin inhibits benzo[a]pyrene-induced DNA adducts in human Hep G2 cells by altering cytochrome P-450 1A1 gene expression. 1069 72

Studies suggest that resveratrol (trans-3,4',5-trihydroxystilbene), which is a diphenolic antioxidant found in plants and foods, has cancer chemopreventive and chemotherapeutic potential. A lower risk of lung cancer among consumers of wine compared with consumers of other beverages has been observed, which may be partly attributed to the high content of resveratrol particularly in red wine. We have studied the effect of resveratrol on the expression of genes involved in the metabolism of polycyclic aromatic hydrocarbons in the human bronchial epithelial cell line BEP2D. Expression of the cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1), microsomal epoxide hydrolase (mEH), and glutathione S-transferase P1 (GSTP1) genes was measured by quantitative reverse transcriptase-polymerase chain reaction. The cells were treated either with benzo[a]pyrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin in the presence or absence of resveratrol. Resveratrol inhibited both the constitutive and the induced expression of CYP1A1 and CYP1B1 in a dose-dependent manner. In contrast, the expression of the mEH gene was increased in response to resveratrol and no change in the expression of GSTP1 was found. The altered gene expression in response to resveratrol was reflected in a reduced overall level of benzo[a]pyrene metabolism. These data indicate that resveratrol may exert lung cancer chemopreventive activity through altering the expression of genes involved in the metabolism of polycyclic aromatic hydrocarbons, resulting in altered formation of carcinogenic benzo[a]pyrene metabolites in human bronchial epithelial cells.
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PMID:Lung carcinogenesis: resveratrol modulates the expression of genes involved in the metabolism of PAH in human bronchial epithelial cells. 1127 1

Adult Atlantic tomcod, Microgadus tomcod, from the Hudson River, New York State, USA, exhibit reduced inducibility of hepatic cytochrome P4501A1 (CYP1A1) mRNA compared with adult tomcod from the cleaner Miramichi River, New Brunswick, Canada, when treated with coplanar polychlorinated biphenyl (PCB) congeners or 2,3,7,8-tetrachlorodibenzo-p-dioxin. In contrast, little difference in CYP1A1 inducibility is observed between tomcod from these two rivers when treated with polycyclic aromatic hydrocarbons (PAHs). We sought to determine if impaired hepatic CYP1A1 inducibility in Hudson River tomcod results from a multigenerational, genetic adaptation or a single generational, physiological acclimation. Embryos and larvae from controlled experimental crosses of Hudson River and Miramichi River parents were exposed for 24 h to water-borne PCB congener 77 (10 ppm), benzo[a]pyrene (BaP; 10 ppm), or dimethysulfoxide, and CYP1A1 expression was assessed in individual larva using competitive reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The CYP1A1 mRNA was significantly induced in larvae from both populations by BaP (47- and 52-fold) and PCB 77 (9- and 22-fold), although levels of expression were higher in offspring of Miramichi matings. Most important, CYP1A1 mRNA was significantly induced by PCB 77 in larvae from Hudson River parents. Concentrations of dioxin, furan, and PCB congeners were measured in livers and eggs of female tomcod from these two locales to quantify the extent of maternal transfer of contaminants. For both rivers, wet-weight contaminant concentrations were significantly higher (4-7 times) in livers than in eggs of the same females, suggesting that a threshold level of contaminants may have to be reached before CYP1A1 transcription is impaired. We conclude that reduced inducibility of hepatic CYP1A1 mRNA in adult tomcod from the Hudson River is most consistent with single-generational acclimation.
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PMID:An evaluation of the etiology of reduced CYP1A1 messenger RNA expression in the Atlantic tomcod from the Hudson River, New York, USA, using reverse transcriptase polymerase chain reaction analysis. 1133 64

The inducibility of cytochrome P4501A1 gene (CYP1A1) expression was examined in human lung samples from 27 subjects, using an explant culture system and semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. CYP1A1 transcripts were present in all of the lung specimens and were induced by the prototypic inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (B[a]P), and by the atypical inducers pyridine, nicotine, and omeprazole. 2-Hydroxypyridine was a better inducer than pyridine, implicating metabolites in CYP1A1 induction by the parent compound. The prototypical inducers were the most effective inducers in many samples but were ineffective in some samples in which the atypical compounds were effective inducers. Cytochrome P4501A2 (CYP1A2) transcripts were also detected in most of the lung specimens and were inducible in some specimens. The results show the suitability of the explant culture system for examining the inducibility of human pulmonary CYP1A1 and CYP1A2, indicate the heterogeneity in individual sensitivity to the induction, and underscore the need to include atypical inducers in studies of CYP1A inducibility in humans.
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PMID:Induction of CYP1A1 and CYP1A2 expressions by prototypic and atypical inducers in the human lung. 1184 38

In fish, the embryos and larvae are the life-stages most sensitive to damage from environmentally borne dioxin-like compounds and polycyclic aromatic hydrocarbons (PAHs). Methods are not routinely available to measure the body burdens of contaminants in embryos and larvae, thus precluding the investigation of links between exposure and biological effects. Quantification of expression of cytochrome P4501A1 (CYP1A1) provides an index of relative exposure of natural populations to bioavailable aromatic hydrocarbons (AH) and an initial evaluation of their biological effects. We developed a quantitative approach to standardize total RNA loading and then used competitive reverse transcriptase-polymerase chain reaction (RT-PCR) to quantify the CYP1A1 mRNA expression in environmentally exposed Atlantic tomcod (Microgadus tomcod) post yolk-sac larvae (postlarvae) from the Hudson River, New York, and in chemically treated postlarval offspring of controlled laboratory crosses of Hudson River parents. Significant induction of CYP1A1 expression was observed in tomcod postlarvae exposed to waterborne 3,3',4,4'-tetrachlorobiphenyl (PCB 77) (four-fold) and benzo[a]-pyrene (eight-fold) compared with vehicle-exposed controls. In contrast, CYP1A1 was not induced in Hudson River-exposed postlarvae compared with vehicle-exposed controls. This study demonstrates the feasibility of using competitive RT-PCR for the measurement of gene expression in environmentally exposed larvae of sentinel species, and is consistent with the hypothesis that postlarvae exposed to the Hudson River environment have not bioaccumulated sufficient levels of AHs to induce CYP1A1 expression. The high levels of hepatic CYP1A1 mRNA expression previously reported in 5-8 month old juvenile tomcod from the Hudson River coincides with their descent to the benthic habitat and the onset of independent feeding on AH-contaminated benthic prey.
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PMID:Cytochrome P4501A1 is induced by PCB 77 and benzo[a]pyrene treatment but not by exposure to the Hudson River environment in Atlantic tomcod (Microgadus tomcod) post-yolk sac larvae. 1210 35

Smoking is a major risk factor for endothelial cell injury and subsequent coronary artery disease. Epidemiological studies implicate the phospholipase A2/arachidonic acid cascade in the mechanism by which smoking causes heart disease. However, specific components of cigarette smoke that activate this pathway have not been identified. The purpose of this study was to investigate the effects of polycyclic aromatic hydrocarbons contained in cigarette smoke on phospholipase A2 (PLA2) activity and apoptosis of human coronary artery endothelial cells. 1-methylanthracene (1-MA), phenanthrene (PA), and benzo(a)pyrene (B(a)P) caused significant release of 3H-arachidonate from endothelial cells. 1-MA and PA, but not B(a)P, also caused significant release of 3H-linoleic acid. Release of fatty acids from membrane phospholipids preceded the onset of apoptosis. 3H-arachidonate release and apoptosis induced by 1-MA, B(a)P, and PA were inhibited by methylarachidonoyl-fluorophosphonate, an inhibitor of Groups IV and VI PLA2s. Bromoenol lactone, an inhibitor of Group VI enzymes, inhibited both 3H-arachidonate release and apoptosis induced by 1-MA and PA, but not B(a)P. MJ33, an inhibitor of the acidic calcium-independent PLA2, attenuated 3H-arachidonate release and apoptosis by PA, but not 1-MA or B(a)P. The presence of Groups IV and VI and the acidic iPLA2 in endothelial cells was demonstrated by reverse transcriptase-polymerase chain reaction and Western analysis. These data suggest that 1-MA, B(a)P and PA induce apoptosis of endothelial cells by a mechanism that involves activation of these three distinct isoforms of PLA2.
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PMID:Polycyclic aromatic hydrocarbons present in cigarette smoke cause endothelial cell apoptosis by a phospholipase A2-dependent mechanism. 1220 49


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