Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pattern of expression of individual cytochrome P450 (CYP) forms participating in the metabolism of xenobiotics is being increasingly well characterised in the human pulmonary tissue. Recent studies using methods having increased sensitivity and specificity, such as the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, have revealed constitutive and inducible expression of several CYP forms in different cell types of the human lung. These studies have revealed the presence of mRNA of several procarcinogen-activating CYP forms in whole lung tissue and alveolar macrophages, including CYP1A1, CYP2B6/7, CYP2E1, and CYP3A5. The results of several studies on CYP2D6 expression have yielded contradictory results. Immunohistochemical analysis shows that CYP3A5 protein is present in all lung samples studied, and is localized in the ciliated and mucous cells of the bronchial wall, bronchial glands, bronchiolar ciliated and terminal cuboidal epithelium, type I and type II alveolar epithelium, vascular and capillary endothelium, and alveolar macrophages. Also CYP3A4 protein is found in some cell types in a minority (about 20%) of lung samples. Primary cultures of freshly isolated broncho-alveolar macrophages as well as a continuously growing bronchial carcinoma cell line (A-549) are being used for CYP induction studies in our laboratory. The results indicate that CYP1 family members are inducible in these cells by polycyclic aromatic hydrocarbon (PAH) inducers, and that CYP3A5, but not CYP3A4, is present constitutively. The results of these studies indicate that several different xenobiotic-metabolizing CYPs are present in the human lung and lung-derived cell lines, possibly contributing to in situ activation of pulmonary procarcinogens. Interindividual differences in the expression of these CYPs may contribute to the risk of developing lung cancer and possibly other pulmonary diseases initiated by agents that require metabolic activation.
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PMID:Expression of xenobiotic-metabolizing CYPs in human pulmonary tissue. 1044 7

Several recent studies have demonstrated that the cytochrome p450 (CYP) family plays an important role in the metabolism of taxanes. However, the role of CYP gene expression in tumors and peripheral mononuclear cells (PMN) is unknown. We therefore investigated the levels of CYP3A4 and CYP2C gene expression using reverse transcription polymerase chain reaction (RT-PCR) in PMN from 16 previously untreated lung cancer patients to determine whether the expression of the two genes is induced by docetaxel (TXT). Neither the CYP3A4 nor the CYP2C gene was induced after administration of carboplatin (CBDCA) alone. Expression of the CYP3A4 gene was induced by the administration of TXT alone or TXT and CBDCA, but expression of the CYP2C gene was unaffected. We also measured the expression of both genes using RT-PCR in 20 autopsy samples (ten non-small-cell lung cancers and their corresponding normal lung tissues) obtained from patients who had not received any chemotherapy during life. The level of CYP2C gene expression in samples of lung cancer was significantly higher than in normal lung tissue, but the level of CYP3A4 gene expression was not. These results suggest that the CYP3A4 gene is induced by TXT, and that it plays an important role in intracellular TXT metabolism.
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PMID:Induction of cytochrome P450 3A4 by docetaxel in peripheral mononuclear cells and its expression in lung cancer. 1148 23

The role of human cytochrome P450 (CYP) in the metabolic activation of tobacco-related N-nitrosamines was examined by Salmonella mutation test using a series of genetically engineered Salmonella typhimurium YG7108 strains each co-expressing a form of CYP (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5) together with human NADPH-cytochrome P450 reductase. Seven tobacco-related N-nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N-nitrosodiethylamine, N-nitrosopyrrolidine, N-nitrosopiperidine, N-nitrosonornicotine, N-nitrosoanabasine, and N-nitrosoanatabine were used. The CYP2A6 was found to be responsible for the mutagenic activation of essentially all tobacco-related N-nitrosamines examined. On the basis of the evidence, genetic polymorphism of the CYP2A6 gene appeared to be one of the factors determining cancer susceptibility caused by smoking. Previously, we found the whole deletion of the CYP2A6 gene (CYP2A6*4C) as a type of genetic polymorphism in Japanese. We hypothesized that individuals possessing the gene homozygous for CYP2A6*4C were incapable of activating tobacco-related N-nitrosamines and showed lower susceptibility to lung cancer induced by tobacco smoke. Thus, the relationship between the CYP2A6*4C and the susceptibility to the lung cancer was evaluated. The frequency of the CYP2A6*4C was significantly lower in the lung cancer patients than healthy volunteers, suggesting that the subjects carrying the CYP2A6*4C alleles are resistant to carcinogenesis caused by N-nitrosamines because of the poor metabolic activation capacity. Taking these results into account, CYP2A6 is an enzyme enhancing lung cancer risk.
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PMID:Role of human cytochrome P450 (CYP) in the metabolic activation of nitrosamine derivatives: application of genetically engineered Salmonella expressing human CYP. 1221 73

CYP3A isozymes are involved in tobacco carcinogen- and steroid-metabolism, and are expressed in human lung tissue showing interindividual variation in expression and activity. The CYP3A4*1B allele has been associated with a two-fold higher promoter activity and with high-grade prostate cancers. The very frequent intron 3 polymorphism in the CYP3A5 gene (CYP3A5*3) results in decreased CYP3A5 protein levels. A case-control study was conducted in 801 Caucasian lung cancer patients that included 330 adenocarcinomas, 260 squamous cell carcinomas, 171 small cell lung cancers (SCLC) and 432 Caucasian hospital-based controls. CYP3A-genotyping was performed by capillary polymerase chain reaction followed by fluorescence-based melting curve analysis. A significantly increased SCLC risk for CYP3A4*1B allele carriers [odds ratio (OR) 2.25, 95% confidence interval (CI) 1.11-4.55, P=0.02] was found. After dividing cases and controls by gender, an increased lung cancer risk for CYP3A4*1B carriers (OR 3.04, 95% CI 0.94-9.90, P=0.06) for women but not for men (OR 1.00, 95% CI 0.56-1.81) was revealed. Heavier smoking men (> or =20 pack-years) with the CYP3A4*1B allele had a significant OR for lung cancer of 3.42 (95% CI 1.65-7.14, P=0.001) compared to *1A/*1A carriers with lower tobacco exposure (<20 pack-years). For women, the respective OR was 8.00 (95% CI 2.12-30.30, P=0.005). Genotype frequencies were generally in Hardy-Weinberg equilibrium, except for CYP3A5 where a greater than expected number of CYP3A5*1 homozygotes was observed among cases (P=0.006). In addition, we observed linkage disequilibrium of CYP3A4 and CYP3A5 (P<0.00001), but a non-significantly increased lung cancer risk was only found for homozygous CYP3A5*1 allele carriers (OR 5.24, 95% CI 0.85-102.28, P=0.14) but not for heterozygotes. To confirm our observation that the CYP3A4*1B allele increases SCLC risk and modifies the smoking-related lung cancer risk in a gender-specific manner, further studies, including CYP3A haplotype analysis, will be necessary.
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PMID:The CYP3A4*1B allele increases risk for small cell lung cancer: effect of gender and smoking dose. 1451 59

Genetic polymorphisms of the human CYP3A family affect clinical drug efficacy and may modify cancer risk. CYP3A genes show high sequence similarity that had previously lead to misallocation of CYP3A polymorphisms. Recent studies indicated a high degree of or even complete linkage for certain CYP3A alleles. Reliable LightCycler-based genotyping methods were developed and their degree of linkage in a large Caucasian population (n = 1210) investigated. Strong linkage disequilibrium was confirmed between CYP3A4, CYP3A5, and CYP3AP1 (each at P < 10(-5)). Contrary to some previous results claiming complete linkage between the phenotypically relevant CYP3A5*1 and a variant in a pseudogene promoter region CYP3AP1*1 we found among 428 controls (15 of 66) and 782 lung cancer cases (25 of 115) approximately 22% of CYP3AP1*1 carriers to be homozygous for CYP3A5*3 We conclude that contrary to previous assumptions, the CYP3AP1 genotype is not a reliable predictor for CYP3A5 activity.
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PMID:Genotype relationships in the CYP3A locus in Caucasians. 1505 Jul 38

(1) Platinum-based chemotherapy is generally used to treat advanced-stage non small-cell lung cancer (stages III and IV), but has only a modest impact on survival. There is no reference treatment. (2) Gefitinib inhibits the tyrosine kinase activity of the receptor for EGF (epidermal growth factor), which is thought to be involved in tumour growth. It has a temporary licence in France and is used on a named-patient basis, but full marketing authorisation has already been granted in Japan, the United States, and elsewhere. (3) Two double-blind dose-finding studies compared two doses of oral gefitinib monotherapy (250 mg/day and 500 mg/day) in patients in whom at least two lines of chemotherapy had failed. The results were favourable, with a median survival of 6 months and a symptomatic improvement in some patients, but they are undermined by the absence of a placebo group and by major protocol violations. (4) Two double-blind trials, each in more than 1000 patients, showed that gefitinib does not increase the efficacy of first-line platinum combinations. (5) About 15% of patients receiving gefitinib monotherapy in clinical trials stopped taking the treatment because of adverse events. The most frequent were gastrointestinal (diarrhea, nausea, vomiting) and cutaneous (rash, acne, dry skin, pruritus). (6) Interstitial pneumonitis occurred in about 1% of patients, and was fatal in about one-third of cases. (7) Gefitinib is metabolised by the cytochrome P450 isoenzyme CYP3A4, so carries a potentially high risk of interactions. (8) In practice, more thorough assessment of gefitinib is needed to determine whether this new drug is beneficial for patients with non small-cell lung cancer. Marketing authorisation is not currently justified.
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PMID:Gefitinib: new preparation. Non small-cell lung cancer: stricter assessment needed. 1549 96

BRG1, also called SMARCA4, is the catalytic subunit of the SWI/SNF chromatin-remodelling complex and influences transcriptional regulation by disrupting histone-DNA contacts in an ATP-dependent manner. BRG1 and other members of the SWI/SNF complex become inactivated in tumours, implying a role in cancer development. To understand the contribution of BRG1 to lung tumourigenesis, we restored BRG1 in H1299 lung cancer cells and used cDNA microarray analysis to identify changes in gene expression. Forty-three transcripts became activated, whereas two were repressed. Chromatin immunoprecipitation of resulting candidate genes revealed that the CYP3A4 and ZNF185 promoters recruited BRG1 and that recruitment to the CYP3A4 promoter was specific to this gene and did not involve the CYP3A5 or CYP3A7 family members. Moreover, specifically BRG1 but not its homologue BRM was recruited to the CYP3A4 and ZNF185 promoters. To explore their potential relevance in lung tumours, levels of CYP3A4 and ZNF185 transcripts were evaluated in seven additional lung cancer cell lines. CYP3A4 was undetectable in any of the lung cancer cells tested, and only the CYP3A5 family member was present in the A549 and Calu-3 cells. In contrast, the amount of ZNF185 transcript clearly varied among lung cancer cell lines and severely reduced levels were observed in BRG1-deficient cells, except those of A427. We extended these observations to 27 lung primary tumours using real-time RT-PCR (TaqMan) and observed that four (15%) and 14 (52%) of them had BRG1 and ZNF185 downregulation, respectively, when compared with normal lung. No significant correlation between reduced levels of BRG1 and ZNF185 was observed, indicating that additional mechanisms to BRG1 inactivation may contribute to the loss of ZNF185 expression in lung tumours. In conclusion, our results provide evidence that transcriptional activation of ZNF185 and CYP3A4 is mediated by direct association of BRG1 with their promoters and also indicate that a decreased level of ZNF185 is a common feature of lung tumours and may be of biological relevance in lung carcinogenesis.
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PMID:Transcriptional targets of the chromatin-remodelling factor SMARCA4/BRG1 in lung cancer cells. 1573 Nov 17

Vinorelbine (VRL) (IV Navelbine) is a semi-synthetic vinca alkaloid, used in therapeutics for the treatment of non-small-cell lung cancer and advanced breast cancer. The aim of this study was to characterize the cytochrome P450 (CYP) isoenzymes involved in VRL metabolism. VRL was incubated at 1.28 x 10(-5) m for 90 min with human hepatic microsomes prepared from 14 donors (one woman and 13 men aged from 27 to 76 years old) and characterized for CYP1A2, CYP2D6, CYP2E1 and CYP3A4 activities. A four-combined-approach study was performed, including correlation between CYP activities and VRL metabolism among the 14 batches of microsomes, inhibition of VRL biotransformation by isoform-selective substrates and by specific inhibitory antibodies, and incubation with supersomes. Analysis of unchanged VRL and its metabolites was performed using an HPLC method coupled with both radioactive and UV detections. No correlation between CYP1A2 or CYP2E1 and VRL metabolism was observed in the 14 batches of microsomes used. A correlation was shown between VRL metabolism and CYP3A4 activity as determined with the dextromethorphan N-demethylase and nifedipine oxidase activities (r(2)=0.80 and 0.59, respectively). These results were strengthened by a correlation between the metabolism extent of VRL and CYP3A4 protein content determined by immunoblotting (r(2)=0.75). Furthermore, VRL biotransformation was inhibited by troleandomycine, the CYP3A4-specific inhibitor substrate (80% of inhibition) and by anti-CYP3A antibodies (36% of inhibition). On the contrary, a low correlation with CYP2D6 activity as determined by dextrometorphan O-demethylation (r(2)=0.31) was established. CYP2D6 supersomes did not metabolize the drug whereas 63.4% of VRL were metabolized by microsomes overexpressing CYP3A4 isoform. These data indicated that CYP3A4 is the main enzyme involved in the hepatic metabolism of VRL in human, whereas CYP2D6 is not involved.
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PMID:Characterization of human cytochrome P450 isoenzymes involved in the metabolism of vinorelbine. 1617 33

The worldwide human exposure to aflatoxin B1 (AFB1), particularly in developing countries, remains to be a serious public health concern. Although AFB1 is best known as a hepatocarcinogen, epidemiological studies have shown a positive association between human lung cancer occurrence and inhalation exposure to AFB1. Cytochrome P450 (CYP)-catalyzed metabolic activation is required for AFB1 to exert its carcinogenicity. Previous studies have identified CYP1A2 and CYP3A4 as the major enzymes for AFB1 activation in human liver. However, the key CYP enzymes in human lung that can efficiently activate AFB1 in situ are unknown. In the present study, we demonstrate that CYP2A13, an enzyme predominantly expressed in human respiratory tract, has a significant activity in metabolizing AFB1 to its carcinogenic/toxic AFB1-8,9-epoxide and AFM1-8,9-epoxide at both low (15 microM) and high (150 microM) substrate concentrations. Under the same conditions, there was no detectable AFB1 epoxide formation by CYP2A6, which was also reported to be involved in the metabolic activation of AFB1. Consistent with the activity data, there was an approximately 800-fold difference in LC50 values of AFB1 (48-hr treatment) between Chinese hamster ovary (CHO) cells expressing CYP2A13 and CYP2A6 (50 nM versus 39 microM). We further demonstrate that amino acid residues Ala117 and His372 in CYP2A13 protein are important for AFB1 epoxidation and its related cytotoxicity. Our results suggest that CYP2A13-catalyzed metabolic activation in situ may play a critical role in human lung carcinogenesis related to inhalation exposure to AFB1.
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PMID:Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract. 1638 75

Cytochrome P450 (CYP) 3A4 is responsible for most CYP3A-mediated drug metabolism but the minor isoforms CYP3A5, CYP3A7 and CYP3A43 also contribute. CYP3A5 is the best studied of the minor CYP3A isoforms. It is well established that only approximately 20% of livers express CYP3A5. The most common reason for the absence of expression is a splice site mutation. The frequency of variant alleles shows interethnic differences, with the wild-type CYP3A5*1 allele more common in Africans than Caucasians and Asians. In individuals who express CYP3A5, the percentage contributed to total hepatic CYP3A by this isoform is still unclear, with estimates ranging from 17% to 50%. CYP3A5 is also expressed in a range of extrahepatic tissues. Only limited information is available on the regulation of CYP3A5 expression but it appears to be inducible via the glucocorticoid receptor, pregnane X receptor and constitutive androstane receptor-beta, as for CYP3A4. Although information on the substrate specificity of CYP3A5 is limited compared with CYP3A4, there have been a number of recent pharmacokinetic studies on a small range of substrates in individuals of known genotype to investigate the contribution of CYP3A5. In the case of midazolam, ciclosporin, nifedipine and docetaxel, clearance by individuals with a CYP3A5-expressing genotype did not differ from that for nonexpressors, but in the case of tacrolimus, eight independent studies have demonstrated faster clearance by those carrying one or two CYP3A5*1 alleles. This may reflect faster turnover of tacrolimus by CYP3A5 than the other substrates. CYP3A5 genotype may affect cancer susceptibility. Certain combined CYP3A4/CYP3A5 haplotypes show differential susceptibility to prostate cancer and there is a nonsignificant increase in the risk of small-cell lung cancer for a CYP3A5*1/*1 genotype. Females positive for CYP3A5*1 appear to reach puberty earlier, which may affect breast cancer risk. CYP3A5*1 homozygotes may have higher systolic blood pressure.CYP3A7 is predominantly expressed in fetal liver but is also found in some adult livers and extrahepatically. The molecular basis for expression in adult liver relates to upstream polymorphisms, which appear to increase homology to CYP3A4 and make regulation of expression more similar. CYP3A7 has a specific role in hydroxylation of retinoic acid and 16alpha-hydroxylation of steroids, and is therefore of relevance both to normal development and carcinogenesis.CYP3A43 is the most recently discovered CYP3A isoform. In addition to a low level of expression in liver, it is expressed in prostate and testis. Its substrate specificity is currently unclear. Polymorphisms predicting absence of active enzyme have been identified.
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PMID:Significance of the minor cytochrome P450 3A isoforms. 1643 Mar 9


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