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Číslo abstraktu: 11
Enzymes of the large and diverse cytochrome P450 (CYP) family are involved in various cellular processes in human. Besides their most discussed role in metabolism of drugs and other xenobiotics, CYPs play an important role in endogenous metabolic pathways including metabolism and/ or biosynthesis of cholesterol and of bile acids, steroids, retinoic acid, vitamin D3, arachidonic acid and its eicosanoid derivatives (e.g. prostaglandins). Mutations or genetic variation of the CYP genes leading to defect of the particular enzymatic activity can result in severe inborn metabolic disorders or significantly altered drug metabolism. Metabolites produced by CYP enzymes can participate on carcinogenesis. An unintended „activation“ of procarcinogens as well as production of reactive intermediates increases genotoxic stress of the cells and may cause tumour initiation. CYP activity also affects inflammatory processes and signalling pathways that control cell cycle and apoptosis, both with implications for tumour promotion and progression. It is obvious that the mechanisms are very complex. Furthermore, even in human there are still quite many orphan CYPs with yet unknown function. Interspecies comparison of CYP genes – proteins – and respective metabolic activities is difficult and the fact that there are thousands of CYPs throughout all kingdoms of life does not make things much easier. However, CYP deorphanization may be a really exciting process.
CYP2W1, a novel human cytochrome P450 form, was first cloned only a few years ago (Karlgren et al., 2006). This interesting CYP was found to be expressed mainly in fetal or neoplastic tissues (especially in colorectal cancer), whereas its expression in healthy adult tissues is rather low. Such an expression pattern makes CYP2W1 a possible therapeutical target. The CYP2W1 gene expression is epigenetically regulated as demonstrated in vitro as well as in colon cancer samples. The expression of CYP2W1 during fetal period also suggests that it could be involved in cell growth or differentiation processes and such a function may be reiterated later in carcinogenesis. Recent studies also evaluate the prognostic value of CYP2W1 expression in colon cancer (higher expression is associated with worse clinical outcome). Only a little information is available on the CYP2W1 active site topology and the substrate binding although a few models were already published. Concerning the metabolic activity, it is reported that CYP2W1 metabolizes benzphetamine and arachidonic acid and activates several procarcinogens, particularly polycyclic aromatic hydrocarbons, which may be of significance in carcinogenic processes. CYP2W1 has been also shown to catalytically activate certain compounds to cytotoxic (antitumour) products so the enzyme could serve as a novel drug target for the treatment of colon cancer.
While there is still a lot of work needed to be done before a successful prodrug can be designed and tested in cancer treatment, there has been done a major progress in terms of CYP2W1 gene and protein characterization. The CYP2W1 gene is polymorphic with several splice variants. There are also several non-synonymous SNPs in the gene that may alter the enzyme function. Interestingly, some of the variant alleles have been shown to be associated with the colorectal cancer risk. The CYP2W1 protein has also several interesting features. Unlike other CYPs, t is oriented towards the lumen of the endoplasmic reticulum where it is available to the glycosylation machinery and it really is glycosylated at position Asn177. The glycosylation may facilitate processing and cell surface expression of the protein and indeed, CYP2W1 (both the glycosylated and non-glycosylated form) was detected on the cell surface. Such an alternative localization can be targeted but it is also an important factor during drug discovery and development.
To conclude, CYP2W1 is a promising object for further research. It has a potential to be both prognostic marker and a therapeutic target for a cytostatic prodrug or maybe a specific antibody in the treatment of colon cancer.
Acknowledgement: The work was supported by the OPVK project CZ.1.07/2.3.00/20.0019, the Swedish Cancer Foundation and the Swedish Research Council.
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Datum přednesení příspěvku: 26. 4. 2013