Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4-Ipomeanol (IPO) is a pulmonary-specific toxin that is metabolically activated by a cytochrome P450 pathway in lung tissue. In this study, IPO metabolism, as determined by measurement of [14C]IPO covalent binding, was evaluated in a diverse sampling of 18 established, human lung cancer cell lines as well as in normal lung tissue and primary lung carcinoma tissue obtained at the time of thoracotomy from 56 patients with lung cancer. [14C]IPO covalent binding in lung cancer cell lines ranged from 248 to 1,047 pmol of bound [14C]IPO per milligram of protein per 30 minutes (mean +/- SE = 547 +/- 62.2). IPO metabolism in normal lung tissue ranged from 12 to 2,007 pmol of covalently bound [14C]IPO per milligram of protein per 30 minutes (mean +/- SE = 549 +/- 60). In lung cancer tissue, values ranged from 0 to 2.566 pmol of covalently bound [14C]IPO per milligram of protein per 30 minutes (mean +/- SE = 547 +/- 60, P greater than .3). When patients were divided into smokers and current non-smokers (no tobacco products smoked for greater than 6 mo), no effects of cigarette smoking were observed for either normal lung tissue or lung tumor tissue (P greater than .1 in all instances). A wide range of IPO metabolic activity was observed among different histological classifications of lung cancer cell lines and of fresh lung cancer tissues. IPO metabolism was simultaneously compared in normal lung tissue and lung cancer tissue from individual patients, but no positive correlation was observed (r = .10; P greater than .30). The results clearly demonstrate a wide range of IPO metabolism in both normal and lung cancer cells and indicate that a wide diversity of human lung cancers possess the metabolic enzyme system(s) necessary for the bioactivation of IPO to a potentially cytotoxic intermediate. Therefore, the continued exploration for any possible therapeutic potential of IPO in patients with lung cancer appears warranted.
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PMID:Metabolic activation of 4-ipomeanol in human lung, primary pulmonary carcinomas, and established human pulmonary carcinoma cell lines. 238 94

The cytochrome P450 (CYP) systems catalyze the metabolic transformation of a wide variety of xenobiotics including procarcinogens present in cigarette smoke condensate as well as atmospheric pollutants. The CYP1A1 isoenzyme is of particular interest because it has been implicated as a risk factor in the etiology of lung cancer in heavy cigarette smokers. The identification and expression of the structural CYP1A1 gene in either normal human lung or lung cancer cells has not been reported. Because of its potential significance in human lung cancer, we investigated the expression of the CYP1A1 structural gene in 24 established human lung cancer cell lines including 15 non-small cell (eight adenocarcinomas, three large cell undifferentiated carcinomas, two bronchioloalveolar cell carcinomas, and two squamous cell carcinomas) and nine small cell lung carcinomas. CYP1A1 mRNA was detected in 14 of 15 (93%) of the non-small cell lung carcinoma cell lines examined following 24-hour treatment with benz[a]anthracene (BA) and in nine of 15 (60%) of the non-small cell lines cultured without an inducer in the medium. When the small cell lung cancer lines were evaluated for CYP1A1 gene expression, two of nine (22%) expressed detectable CYP1A1 mRNA in both BA-induced cell cultures and constitutive (control) cultures. A positive correlation was noted between BA-induced CYP1A1 mRNA levels and the corresponding aryl hydrocarbon hydroxylase activity expressed as absolute BA-induced enzyme activity (r = 0.74; P less than .01; n = 24), which further demonstrated that CYP1A1 mRNA expression reflects CYP1A1 enzyme activity in the individual cell lines. These observations represent the first known demonstration of constitutive (non-induced) CYP1A1 gene expression in human cells and suggest altered regulation of the CYP1A1 gene in selected lung cancer cell lines. These human pulmonary carcinoma cell lines, which have documented regulatory defects, could be useful for further identification of the mechanisms associated with CYP1A1 gene regulation.
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PMID:Altered regulation of the cytochrome P4501A1 gene: novel inducer-independent gene expression in pulmonary carcinoma cell lines. 255 30

p53 inhibits cell cycle progression and DNA damaging cytostatics induce p53 protein expression, indicating that p53 responds to DNA damage. We have measured benzo[a]pyrene (BP)-induced DNA damage in association with p53 expression. The most relevant DNA adducts for carcinogenesis, benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA adducts, were measured by synchronous fluorescence spectrophotometry and p53 immunohistochemistry using polyclonal antibody CM1, which detects both wild-type and mutated forms of p53. Activation of BP in A-549 lung carcinoma and MCF-7 breast adenocarcinoma cell lines containing wild-type p53 was followed by an increase in p53 protein expression. alpha-Naphthoflavone, an inhibitor of cytochrome P450 (CYP)1A1, decreased both the formation of diolepoxide metabolites and the p53 response. The cell lines not able to activate BP, A-427 and SK-LU-1 (both human lung carcinomas), SK-MES-1 (human lung squamous carcinoma) and human fibroblasts, did not show any increase in p53 immunohistochemistry. The OVCAR-3 ovarian adenocarcinoma cell line, containing a mutation in exon 7 of p53, and the SK-LU-1 cell line expressed very high levels of p53 protein before BP treatment and no increase in p53 immunohistochemistry was seen. These findings indicate that p53 protein is part of the response of the cells to BP-induced DNA damage.
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PMID:p53 protein expression is correlated with benzo[a]pyrene-DNA adducts in carcinoma cell lines. 755 63

Extrarenal 25-hydroxyvitamin D3-1alpha-hydroxylase is believed to play a major role in the pathogenesis of hypercalcemia associated with various types of granulomatous and lymphoproliferative diseases and certain solid tumors. In this paper, we describe the cloning of the cytochrome P450 component of the extrarenal enzyme from a human nonsmall cell lung carcinoma, SW 900. The cytochrome P450 for the extrarenal 1alpha-hydroxylase has an amino acid sequence identical to that of the cytochrome P450 component of the CYP1alpha, the renal form of the enzyme, and appears to be a product of the same gene. CYP1alpha messenger RNA (mRNA) and 1alpha-hydroxylase enzyme activity were detected in two (SW 900, SK-Luci-6) of a series of five nonsmall cell lung carcinoma cell lines. All five lung cell lines were cultured with the same medium under the same conditions, but only two of the five expressed 1alpha-hydroxylase enzyme; two others (WT-E, Calu-1) expressed high levels of the reciprocally regulated enzyme, 25-hydroxyvitamin D3-24-hydroxylase, with its specific cytochrome P450 component, CYP24. Although under basal conditions the lung cell line SW 900 expressed only CYP1alpha and showed 1alpha-hydroxylase enzyme activity, when treated with small concentrations of 1alpha,25-dihydroxyvitamin D3 or high concentrations of 25-hydroxyvitamin D3, it began to express CYP24 and exhibit 24-hydroxylase enzyme activity. Somewhat surprisingly, SW 900 cells still had detectable CYP1alpha mRNA some 24 h after vitamin D treatment despite the fact that 1alpha-hydroxylase enzyme activity was unmeasurable. These data are consistent with the emerging hypothesis that vitamin D through its active form does not directly turn off CYP1alpha mRNA production but, rather, strongly stimulates CYP24, thereby masking CYP1alpha activity. The factor(s) responsible for the basal expression of CYP1alpha in SW 900 and SK-Luci-6 is currently unknown.
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PMID:Expression and activity of vitamin D-metabolizing cytochrome P450s (CYP1alpha and CYP24) in human nonsmall cell lung carcinomas. 1038 27

The present study has determined the effects of 6-nitrochrysene (6-NC) on human cytochrome P450-dependent monooxygenases in human hepatoma HepG2 cells. Treatment of HepG2 cells with 6-NC increased the activities of microsomal benzo[a]pyrene hydroxylase, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylases, cytosolic glutathione S-transferase and N-acetyltransferase, and S9 metabolic activation of 6-NC in the Ames mutagenicity test. Immunoblot and RNA blot analyses revealed that 6-NC induced CYP1A1 protein and mRNA levels in the hepatoma cells. Nuclear transcription assay demonstrated that 6-NC increased the transcription rate of CYP1A1 gene in HepG2 cells. Treatment of human lung carcinoma NCI-H322 cells with 6-NC increased benzo[a]pyrene hydroxylase activity and CYP1A1 protein and mRNA levels. These results demonstrate that 6-NC is an inducer of human CYP1A1 and the induction occurs at a transcriptional level in HepG2 cells. The ability of 6-NC to induce liver and lung CYP1A1 may be an important factor to consider in assessing 6-NC metabolism and toxicity in humans.
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PMID:Induction of cytochrome P450 1A1 in human hepatoma HepG2 cells by 6-nitrochrysene. 1103 35

Multidrug resistance may be conferred by P-glycoprotein (Pgp, ABCB1) or the multidrug resistance associated protein (MRP). These membrane proteins are members of the ATP binding cassette transporter superfamily and are responsible for the removal from the cell of several anticancer agents including doxorubicin. Modulators can inhibit these transporters. LY335979 is among the most potent modulators of Pgp with a Ki of 59 nM. LY335979 is selective for Pgp, and does not modulate MRP-mediated resistance by MRP1 (ABCC1) and MRP2 (ABCC2). LY335979 significantly enhanced the survival of mice implanted with Pgp-expressing murine leukemia (P388/ADR) when administered in combination with either daunorubicin, doxorubicin or etoposide. Coadministration of LY335979 with paclitaxel compared to paclitaxel alone significantly reduced the tumor mass of the Pgp-expressing UCLA-P3.003VLB lung carcinoma in a xenograph model and delayed the development of tumors in mice implanted with the parental drug-sensitive UCLA-P3 tumor. LY335979 was without significant effect on the pharmacokinetics of these anticancer agents. This may be due impart to its poor inhibition of four major cytochrome P450 isozymes important in metabolizing doxorubicin and other oncolytics. The selectivity and potency of this modulator allows the clinical evaluation of the role of Pgp in multidrug resistance. LY335979 is currently in clinical trials.
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PMID:Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic. 1117 91

Emodin (3-methyl-1,6,8-trihydroxyanthraquinone) is an active compound of many laxative herbal drugs. The present study aimed to determine the effects of emodin on cytochrome P450 (P450)-dependent monooxygenases of human lung adenocarcinoma CL5 cells. Treatment of CL5 cells with 100 microM emodin for 24 h induced benzo[a]pyrene hydroxylation, 7-ethoxyresorufin O-deethylation, and 7-ethoxycoumarin O-deethylation activities of S9 fractions. Immunoblot analysis of CL5 S9 proteins revealed that emodin induced proteins immunorelated to P450s 1A1 and 1B1. Northern blot analysis of total cellular RNA showed that emodin induced P450s 1A1 and 1B1 mRNA levels in CL5 cells. These inductive effects on P450 monooxygenase activity, protein, and mRNA were concentration- and time-dependent. Addition of emodin to CL5 cell microM S9 inhibited its 7-ethoxycoumarin O-deethylation activity. Treatment of CL5 cells with 10 microM 3-methylcholanthrene for 24 h induced monooxygenase activity and P450s 1A1 and 1B1 proteins and mRNA levels. Treatment of the lung cells with 100 microM emodin or purpurin (1,2,4-trihydroxyanthraquinone) for 24 h produced greater induction of P450s 1A1 and 1B1 mRNA than did anthraflavic acid (2,6-dihydroxyanthraquinone) or anthraquinone. The emodin treatment induced P450s 1A1 and 1B1 mRNA in human lung carcinoma NCI-H322 and breast cancer MCF-7 cells. Emodin induced P450 1A1, but not 1B1, mRNA in human hepatoma HepG2 cells. The present study demonstrates that emodin is an inducer of P450s 1A1 and 1B1 protein and mRNA in human lung adenocarcinoma CL5 cells. Modulation of P450 by emodin may be an important factor affecting metabolism and toxicity of the hydroxyanthraquinone in humans.
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PMID:Induction of cytochromes P450 1A1 and 1B1 by emodin in human lung adenocarcinoma cell line CL5. 1150 33

The effect of airborne frying-meat emission particulate (FMEP) on cytochrome P450 (P450)-dependent monooxygenase was determined using human lung adenocarcinoma cell line CL5 treated with organic extract of FMEP prepared from beef, fish or pork. Treatment with fish FMEP extract caused greater increases of intracellular peroxide production and glutathione content than did beef and pork FMEP extracts. Treatment with 200 microg/ml beef, fish or pork FMEP extract for 6 h increased benzo[a]pyrene hydroxylase, 7-ethoxyresorufin and methoxyresorufin O-dealkylases activities in S9. Immunoblot analysis of S9 proteins from control cells and cells treated with FMEP extracts revealed that the airborne particulates increased proteins immunorelated to CYP1A1 and CYP1B1. Northern blot analysis of total cellular RNA from controls and cells treated with FMEP extracts showed that the cooking by-products increased the levels of CYP1A1 and CYP1B1 mRNA. Treatment with 1 microM dibenzo[a,h]anthracene for 6 h increased monooxygenase activities, CYP1A1 and CYP1B1 protein and mRNA levels in CL5 cells. Beef FMEP extract and dibenzo[a,h]anthracene also induced CYP1A1 and CYP1B1 in human lung carcinoma NCI-H322 cells. The present finding demonstrates that airborne particulates generated during the frying of beef, fish and pork can induce carcinogen-metabolizing CYP1A1 and CYP1B1 in the human lung-derived cell line CL5.
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PMID:Induction of cytochromes P450 1A1 and 1B1 in human lung adenocarcinoma CL5 cells by frying-meat emission particulate. 1195 71

Nitropolycyclic aromatic hydrocarbons (NPAHs) are found in diesel exhaust and ambient air. NPAHs as well as polycyclic aromatic hydrocarbons (PAHs) are known to have mutagenicity, carcinogenicity, and endocrine-disruptive effects. In the present study, the inducibility of the human cytochrome P450-1 (CYP1) family by NPAHs was compared with those produced by their parent PAHs and some reductive metabolites, amino-PAHs. Furthermore, to investigate the differences in the inducibility of the CYP1 family in human tissues, various human tissue-derived cell lines, namely HepG2 (hepatocellular carcinoma), ACHN (renal carcinoma), A549 (lung carcinoma), MCF-7 (breast carcinoma), LS-180 (colon carcinoma), HT-1197 (bladder carcinoma), HeLa (cervix of uterus adenocarcinoma), OMC-3 (ovarian carcinoma), and NEC14 (testis embryonal carcinoma), were treated with NPAHs, PAHs, or amino-PAHs. The mRNA levels of CYP1A1, CYP1A2, and CYP1B1 were determined with reverse transcription-polymerase chain reaction (RT-PCR). The cell lines were classified into two groups: CYP1 inducible cell lines, comprising HepG2, MCF-7, LS-180, and OMC-3 cells, and CYP1 non-inducible cell lines, comprising ACHN, A549, HT-1197, HeLa, and NEC14 cells. In inducible cell lines, the induction profile of chemical specificity was similar for CYP1A1, CYP1A2, and CYP1B1, although the extent of induction differed among the cell lines and for the CYP isoforms. Pyrene, 1-nitropyrene, 1-aminopyrene, 1,3-, 1,6-, and 1,8-dinitropyrenes slightly induced CYP1 mRNAs, but 1,3-dinitropyrene produced a 6-fold induction of CYP1A1 mRNA in MCF-7 cells. 2-Nitrofluoranthene and 3-nitrofluoranthene exhibited stronger inducibility than fluoranthene in the inducible cell lines. 6-Nitrochrysene induced CYP1 mRNAs to the same extent or more potently than chrysene. The induction potencies of 6-nitrobenzo[ a]pyrene and 7-nitrobenz[ a]anthracene were weaker than those of their parents benzo[ a]pyrene and benz[ a]anthracene, respectively. This study demonstrated that NPAHs as well as PAHs induced human CYP1A1, CYP1A2, and CYP1B1 in a chemical-, CYP isoform-, and cell-specific manner. Furthermore, the cell-specific induction of the CYP1 family was not related to the expression levels of aryl hydrocarbon receptor, aryl hydrocarbon nuclear translocator, or estrogen receptors alpha and beta.
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PMID:Induction of CYP1A1, CYP1A2, and CYP1B1 mRNAs by nitropolycyclic aromatic hydrocarbons in various human tissue-derived cells: chemical-, cytochrome P450 isoform-, and cell-specific differences. 1210 46

Interindividual differences in the expression of carcinogen-metabolizing enzymes in the lung may modify the effective dose of tobacco carcinogens in this organ. We investigated the role of detoxifying glutathione S-transferases (GST) in the formation of aromatic DNA adducts in bronchoalveolar macrophages (BAM) of active smokers. The effect of GSTs on aromatic DNA adducts was studied separately and in combination with the PAH-metabolizing cytochrome P450 enzyme, CYP3A. GSTA, GSTM3, GSTP, and CYP3A protein levels were analyzed by Western blotting, GSTM1 and GSTP1 genotypes were determined by polymerase chain reaction (PCR) based methods, and numbers of aromatic DNA adducts were measured by nuclease P1 enhanced 32P-postlabeling method in BAM of 31 active smokers. No correlation was observed between GSTA or GSTP proteins or GSTM1 or GSTP1 genotypes and the level of aromatic DNA adducts. A high or medium expression level of GSTM3 was associated with a lower level of aromatic DNA adducts in the smokers who smoked less than 20 cigarettes per day, when the effect of GSTM3 was analyzed in combination with CYP3A (regression analysis; F(6,24)=6.3, P<0.001). No protection by GSTM3 was observed in heavy smokers. High CYP3A levels, on the other hand, increased the number of DNA adducts regardless of the amount of smoking.
Lung Cancer 2003 Mar
PMID:Glutathione S-transferases and aromatic DNA adducts in smokers' bronchoalveolar macrophages. 1260 64


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