Analysis of CYP2D6 expression in human lung: implications for the association between CYP2D6 activity and susceptibility to lung cancer

Kt, Kivistö; Eu, Griese; Stüven, Thomas; Fritz, Péter; Friedel, Godehard; Hk, Kroemer; Um, Zanger

doi:10.1097/00008571-199708000-00004

Cited by 24 publications

(9 citation statements)

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“…However, recent larger and better designed studies have shown no apparent association and meta analysis also suggests the absence of a signi®cant effect [39±42]. In view of what is now known about the substrate speci®city of CYP2D6 [43] and the fact that it is apparently not expressed in the lung [44], the recent ®ndings on CYP2D6 and lung cancer are not surprising and CYP2D6 now seems a poor candidate gene for this disease.…”

Section: Case-control Studies On Genes Encoding Enzymes Of Xenobioticmentioning

confidence: 99%

Candidate gene case‐control association studies: advantages and potential pitfalls

Daly

Day

2001

Brit J Clinical Pharma

150

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There is increasing information on the importance of genetic polymorphisms in human genes. Polymorphisms occur on average once every 500±1000 base pairs in the human genome and are useful in the identi®cation of genes involved in human disease. Some genetic polymorphisms have functionally signi®cant effects on the gene product and are the most useful type of polymorphism in disease association studies while others are simply useful markers. There are two main approaches using polymorphisms in the identi®cation of genes involved in polygenic diseases. The ®rst involves examining inheritance patterns for genetic polymorphisms in family studies and the second case-control studies which compare genotype frequencies for candidate disease genes in unrelated individuals with the disease and healthy controls. Use of family studies is generally the preferred approach but this is only feasible if the genetic component of the disease is relatively strong, DNA samples are available from other family members and the disease is relatively easy to diagnose and is not stigmatized. Population case-control studies are useful both as an alternative and an adjunct to family studies. When performing case-control studies factors such as study design, methods for recruitment of cases and controls, functional signi®cance of polymorphisms chosen for study and statistical analysis of data require close attention to ensure that only genuine associations are detected. To illustrate some potential problems in the design and interpretation of association studies, some speci®c examples of association studies on drug response and on disease susceptibility involving receptor genes, cytochrome P450 and other xenobiotic metabolizing enzyme genes and immune system genes including TNF-a, IL-10 and the IL-4 receptor are discussed.

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Section: Case-control Studies On Genes Encoding Enzymes Of Xenobioticmentioning

confidence: 99%

Candidate gene case‐control association studies: advantages and potential pitfalls

Daly

Day

2001

Brit J Clinical Pharma

150

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“…CYP1A2, CYP2A6, CYP2A7, CYP2A13, CYP2F1, and CYP4B1 mRNAs were not detected at this level of sensitivity, which yielded clearly visible amplification products for each CYP in human liver or human alveolar macrophage (for CYP2F1 and CYP4B1) cDNA (data not shown). CYP2D6 amplification yielded multiple bands of different sizes, possibly reflecting the expression of pseudogenes and aberrantly spliced mRNAs (2,30).…”

Section: Expression Of Cyp Mrnas In A549 Cellsmentioning

confidence: 99%

Induction and Regulation of Xenobiotic-Metabolizing Cytochrome P450s in the Human A549 Lung Adenocarcinoma Cell Line

Hukkanen

Lassila

Päivärinta

et al. 2000

Am J Respir Cell Mol Biol

144

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Several cytochrome P450 (CYP) enzymes are expressed in the human lung, where they participate in metabolic inactivation and activation of numerous exogenous and endogenous compounds. In this study, the expression pattern of all known xenobiotic-metabolizing CYP genes was characterized in the human alveolar type II cell-derived A549 adenocarcinoma cell line using qualitative reverse transcriptase/polymerase chain reaction (RT-PCR). In addition, the mechanisms of induction by chemicals of members in the CYP1 and CYP3A subfamilies were assessed by quantitative RT-PCR. The expression of messenger RNAs (mRNAs) of CYPs 1A1, 1B1, 2B6, 2C, 2E1, 3A5, and 3A7 was detected in the A549 cells. The amounts of mRNAs of CYPs 1A2, 2A6, 2A7, 2A13, 2F1, 3A4, and 4B1 were below the limit of detection. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced CYP1A1 and CYP1B1 mRNAs 56-fold and 2.5-fold, respectively. CYP3A5 was induced 8-fold by dexamethasone and 11-fold by phenobarbital. CYP3A4 was not induced by any of the typical CYP3A4 inducers used. The tyrosine kinase inhibitor genistein and the protein kinase C inhibitor staurosporine blocked TCDD-elicited induction of CYP1A1, but they did not affect CYP1B1 induction. Protein phosphatase inhibitors okadaic acid and calyculin A enhanced TCDD-induction of CYP1B1 slightly, but had negligible effects on CYP1A1 induction. These results suggest that CYP1A1 and CYP1B1 are differentially regulated in human pulmonary epithelial cells and give the first indication of the induction of CYP3A5 by glucocorticoids in human lung cells. These results establish that having retained several characteristics of human lung epithelial cell CYP expression, the A549 lung cell line is a valuable model for mechanistic studies on induction of the pulmonary CYP system.

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“…CYP2D6 mRNA was first analyzed by Northern blotting of liver RNA leading to the discovery of several splice variants (14). Although these splice variants were confirmed by reverse transcriptase (RT)-PCR to occur also in breast, lung, and brain tissue, they appeared to be in part products of the CYP2D7P pseudogene and their relevance remained unclear (15)(16)(17)(18). Andersen et al (19) as well as Rodriguez-Antona et al (20) developed quantitative RT-PCR assays to quantitate several cytochrome P450 transcripts including CYP2D6 in human liver but the relevance of the CYP2D6 genotype remained uninvestigated.…”

mentioning

confidence: 99%

“…In two earlier studies, CYP2D6 mRNA was semiquantitatively determined in bladder mucosa and in peripheral blood mononuclear cells and found to be correlated to the debrisoquine oxidation phenotype (21,22). CYP2D6 transcripts were also detected by RT-PCR in human placenta (23) and in brain (18) and conflicting results were reported for lung (15,24). A general problem for the quantitative assessment of CYP2D6 transcripts represents the possible expression of the highly homologous CYP2D7 and CYP2D8 pseudogenes which may confound the results.…”

mentioning

confidence: 99%

Discriminative Quantification of Cytochrome P4502D6 and 2D7/8 Pseudogene Expression by TaqMan Real-Time Reverse Transcriptase Polymerase Chain Reaction

Endrizzi

Fischer

Klein

et al. 2002

Analytical Biochemistry

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Analysis of CYP2D6 expression in human lung: implications for the association between CYP2D6 activity and susceptibility to lung cancer

Cited by 24 publications

References 0 publications

Candidate gene case‐control association studies: advantages and potential pitfalls

Candidate gene case‐control association studies: advantages and potential pitfalls

Induction and Regulation of Xenobiotic-Metabolizing Cytochrome P450s in the Human A549 Lung Adenocarcinoma Cell Line

Discriminative Quantification of Cytochrome P4502D6 and 2D7/8 Pseudogene Expression by TaqMan Real-Time Reverse Transcriptase Polymerase Chain Reaction

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