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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Both simultaneous and sequential exposure to arsenite and benzo[a]pyrene (BaP) potentially occur in human populations drinking arsenic-contaminated water or burning arsenic-contaminated coal. Although arsenite and BaP are both well-documented hazardous substances and human carcinogens, interactions between these two agents have not been well defined. In this study, we demonstrated that posttreatment with arsenite synergistically enhanced the cytotoxicity of BaP for a human lung adenocarcinoma cell line, CL3. In contrast, pretreatment of CL3 cells with arsenite attenuated BaP cytotoxicity. Involvement of heat-shock protein 70 and heme oxygenase-1 in this arsenite-mediated attenuation of BaP cytotoxicity was ruled out. Our data also indicated that arsenite pretreatment did not affect the BaP-mediated induction of CYP1A1, the initial enzyme involved in its metabolic activation, but did result in a significant decrease in mRNA and protein levels of cyclooxygenase-2 (COX-2), which is required to convert the BaP metabolite BaP 7,8-dihydrodiol to the ultimate epoxide. In contrast to the high susceptibility of CL3 cells to BaP, the human lung carcinoma cells, H460, and CL3R15 cells (arsenic-resistant CL3 cells) showed normal CYP1A1 inducibility by BaP, had negligible amounts of COX-2, and were highly resistant to BaP. The involvement of COX-2 in BaP activation was confirmed by transfection of H460 cells with a recombinant adenovirus, Ad-pgk-Cox2, coding for COX-2, which resulted in a significant increase in the levels of the COX-2 product prostaglandin E2 in the medium and in the susceptibility of H460 cells to BaP. The present study confirms the importance of COX-2 in BaP activation and demonstrates that the arsenite-mediated attenuation of BaP cytotoxicity is mediated by a reduction in COX-2 levels.
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PMID:Arsenite pretreatment attenuates benzo[a]pyrene cytotoxicity in a human lung adenocarcinoma cell line by decreasing cyclooxygenase-2 levels. 1191 89

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

Lung adenocarcinoma has replaced squamous cell lung carcinoma as the most frequent histological subtype in lung cancers. However, genetic factors that affect cancer susceptibility are much less understood in adenocarcinoma than in squamous cell carcinoma. In this study, polymorphisms in five genes involved in the metabolism of carcinogens or in the repair of damaged DNA in lung cells, NQO1-Pro187Ser, GSTT1-positive/null, GSTM1-positive/null, CYP1A1-Ile462Val, and OGG1-Ser326Cys, were examined for association with lung adenocarcinoma risk in a case-control study of 198 patients and 152 control subjects. The NQO1 and GSTT1 polymorphisms were associated with lung adenocarcinoma risk with adjusted odds ratio of 2.15 for the NQO1-Pro/Pro genotype versus the Ser/Ser genotype and adjusted odds ratio of 1.61 for the GSTT1-null genotype versus the positive genotype, respectively. Furthermore, individuals with the combined genotype of NQO1-Pro/Pro and GSTT1-null showed greater risk compared with those of NQO1-Ser/Ser and GSTT1-positive. In contrast, significant association was not observed for the GSTM1, CYP1A1, and OGG1 polymorphisms with lung adenocarcinoma risk, although several studies have shown their implication in the risk for squamous cell lung carcinoma. The result indicates that the NQO1-Pro/Pro and GSTT1-null genotypes are risk factors for lung adenocarcinoma development, and that the genetic factors for susceptibility to adenocarcinoma are different from those to squamous cell carcinoma. The enhanced risk of the NQO1-Pro/Pro genotype combined with the GSTT1-null genotype was more evident in smokers than in nonsmokers. Therefore, carcinogens in tobacco smoke, which are activated by NQO1 and detoxified by GSTT1, could have a role in lung adenocarcinoma development.
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PMID:Contribution of the NQO1 and GSTT1 polymorphisms to lung adenocarcinoma susceptibility. 1216 26

Epidemiological and biochemical studies have indicated that females may be at greater risk of smoking associated lung cancer compared with males. Among lung cancer patients, female smokers have been found to have higher levels of PAH-related DNA adducts and CYP1A1 gene expression in their normal lung tissue compared to male smokers. A possible role of steroid hormones in these sex differences via interactions between aryl hydrocarbon receptor and estrogen receptor mediated cellular effects has been suggested. In the present study the impact of the estrogen receptor (ERalpha) on CYP1A1 and CYP1B1 gene expression was studied in vitro in human bronchial epithelial cells. Transient transfection of the BEP2D cell line with ERalpha influenced neither constitutive expression of CYP1A1 or CYP1B1 nor induction of these genes by TCDD as measured by real-time RT-PCR. ERalpha had no effect on the constitutive or TCDD-induced enzymatic activity of CYP1A1 (EROD). We also studied the effect of steroid hormones on lung PAH metabolic activation in A/J mice. Intact and ovariectomized female mice were orally exposed to a single dose of benzo[a]pyrene. Ovariectomy did not influence the levels of either benzo[a]pyrene-derived protein or DNA adducts in the lung tissue measured by HPLC and 32P-postlabeling, respectively. In conclusion, the present data do not support the hypothesis of a role of estrogen or the ERalpha in regulating the metabolic activation of polycyclic aromatic hydrocarbons in lung.
Lung Cancer 2004 Sep
PMID:Role of estrogen receptor in regulation of polycyclic aromatic hydrocarbon metabolic activation in lung. 1530 69

Hepatocytes are an important physiological model for evaluation of metabolic and biological effects of xenobiotics. They do not proliferate in culture and are extremely sensitive to damage during freezing and thawing, even after the addition of classical cryoprotectants. Thus improved cryopreservation techniques are needed to reduce cell injury and functional impairment. Here, we describe a new and efficient cryopreservation method, which permits long-term storage and recovery of large quantities of healthy cells that maintain high hepatospecific functions. In culture, the morphology of hepatocytes cryopreserved with wheat protein extracts (WPE) was similar to that of fresh cells. Furthermore, hepatospecific functions such as albumin secretion and biotransformation of ammonium to urea were well maintained during 4 days in culture. Inductions of CYP1A1 and CYP2B in hepatocytes cryopreserved with WPEs were similar to those in fresh hepatocytes. These findings clearly show that WPEs are an excellent cryopreservant for primary hepatocytes. The extract was also found to cryopreserve other human and animal cell types such as lung carcinoma, colorectal adenocarcinoma, Chinese hamster ovary transfected with TGF-b1 cDNA, cervical cancer taken from Henrietta Lacks, intestinal epithelium, and T cell leukemia. WPEs have potential as a universal cryopreservant agent of mammalian cells. It is an economic, efficient and non-toxic agent.
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PMID:Wheat extracts as an efficient cryoprotective agent for primary cultures of rat hepatocytes. 1692 46

Polymorphisms in CYP1A1 and CYP1B1 genes in humans are associated with reduction of enzymatic activity towards several substrates, including those found in tobacco smoke. To investigate the potential role these polymorphisms have as modulators of early-onset lung cancer risk, a population-based case-control study involving early-onset lung cancer cases was performed. Biological samples were available for 383 individuals diagnosed prior to 50 years of age identified from the metropolitan Detroit Surveillance, Epidemiology and End Results (SEER) program and 449 age, race and sex-matched controls ascertained through random digit dialing. Genotype frequencies varied significantly by race for CYP1A1 Ile(462)Val and CYP1B1 Leu(432)Val genotypes, so all analyses were stratified by race. No association was seen between lung cancer risk and polymorphisms in CYP1A1 Msp1 or CYP1B1 Leu(432)Val for Caucasians or African Americans, after adjusting for age at diagnosis, sex, pack years of smoking and family history of lung cancer. In Caucasians, those with the IIe/Val genotype at CYP1A1 Ile(462)Val locus were at decreased risk of having lung cancer compared to those with the lle/lle genotype, after adjusting for age at diagnosis, sex, pack years of smoking and family history of cancer (OR=0.41 95% Cl 0.19-0.90). These results were not replicated among the African American population, nor were they modified by amount of smoking.
Lung Cancer 2007 Mar
PMID:Combinations of cytochrome P-450 genotypes and risk of early-onset lung cancer in Caucasians and African Americans: a population-based study. 1717 38

Various molecular epidemiological studies have been performed to find genetic etiology for lung cancer. Particularly, genetic polymorphisms in NAD(P)H-quinone oxidoreductase (NQO1), cytochrome P450 (CYP)1A1, myeloperoxidase (MPO), glutathione-S-transferase (GST)P1, GSTT1, and GSTM1, and have been suspected to affect lung cancer risk. However, there was no study that examined the combined effects of these genes on lung cancer risk. We studied the combined genetic effects on lung cancer risk in 671 Korean subjects including 318 lung cancer patients and 353 controls. They filled questionnaires, which included lifestyle and childhood- and current environment data. Based on single nucleotide polymorphisms and gene deletions, genetic polymorphisms of the above six genes were determined with PCR-RFLP and TaqMan methods. As results, genetic polymorphisms in the GSTP1, MPO, and CYP1A1 among the genetic factors showed associations with lung cancer risk. The reference, which is supposed to have the lowest risk for cancer, was subjects who were homozygous wild type of the GSTP1 and CYP1A1 and had the MPO- mutant allele. After combination study of the three gene-polymorphism, the subjects who were most different with the reference, i.e. had the mutant allele of the GSTP1 and CYP1A1 and homozygous wild type of the MPO, showed approximately 5-fold-higher risk for lung cancer than the reference (95% CI, 2.05-12.05). Therefore, our study suggests that the combination of the GSTP1, MPO, and CYP1A1 variations affects susceptibility to lung cancer.
Lung Cancer 2007 Aug
PMID:Combined effects of genetic polymorphisms in six selected genes on lung cancer susceptibility. 1742 72


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