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Expression analysis of drug-metabolizing enzymes in human keratinocytes after treatment with selected xenobiotics

Project

Food and consumer protection

This project contributes to the research aim 'Food and consumer protection'. Which funding institutions are active for this aim? What are the sub-aims? Take a look:
Food and consumer protection


Project code: BfR-PRS-08-1322-359-09
Contract period: 01.01.2009 - 31.12.2010
Purpose of research: Applied research

Toxification of xenobiotic compounds usually requires enzymatic conversion by metabolizing enzymes. For benzo[a]pyrene (BaP) we have demonstrated that metabolite patterns differ significantly in keratinocytes from other cell lines, such as lung carcinoma A549 or HepG2 cells. This observation is important, as BaP is known to be metabolized by the same enzymes in all of these cells, i.e. CYP1A1, CYP1B1 (Luch, 2004). It indicates that tissue-specific differences may apply in respect to enzyme expression levels and activities. We have further demonstrated a strong induction of CYP1A1 and 1B1 protein levels by western blot. Experiments to determine the enzymatic activities of selected CYPs (CYP1A1, 1A2, 2A6, 3A4, 1B1, 2B6, 2C9, 2C8, 2D6, 2E1) are scheduled for the next funding period. Further studies on CYP functions will be focused on CYP1A1 and 1B1. Firstly, we will investigate whether exogenous factors or cytokines affect both CYP expression and activities in human keratinocytes. Next, we will determine by EROD assays, whether metabolic activities of these enzymes depend on the duration of culture or age. Beside human keratinocytes, we will also include human 3D skin models and differentiated keratinocytes in our investigation. Further, we have recently observed that exposure to coumarin can inhibit the expression of CYP1A1, leading to the question whether the same regulation applies to CYP1B1 and whether coumarin interferes with the aryl hydrocarbon receptor (AhR) and/or other toxico-logical effects of PAH.Furthermore, we will pursue on examinations of BaP metabolite pattern formation in the next year. Since some metabolites, e.g. BaP-7,8-Dihydrodiol, are preferentially detected in human 3D skin models but hardly in keratinocytes, it requires further attention whether differentiation of human keratinocytes can alter metabolism of certain reference compounds. The corresponding analysis of human skin samples is also foreseen.

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Subjects

Framework programme

BMEL Frameworkprogramme 2008

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