Abstract
Effect of cyclosporin A (CsA) in a therapeutic concentration, on the expression of cytochrome P450 genes (CYPs), was investigated in normal human dermal fibroblast cells. The expression of 57 genes, encoding cytochrome P450 isoforms, was estimated using the microarray method. Amongst 396 normalized fluorescence signals related to cytochrome P450 activity, only 91 were strictly connected to CYPs and were analyzed using two methods: a self-organizing feature map of artificial neural networks and typical statistical analysis with significance level at p ≤ 0.05. Comparing the samples from fibroblasts cultured with CsA and those cultured without, up-regulated changes of CYP19A1, 1B1, 7A1, 7F1, 17A1 and down-regulated 2D6 gene expression were observed. The mRNAs with increased changes were in the same neuron of the self-organizing feature map. All distinguished CYPs encode monooxygenases, which plays an important role in steroids biosynthesis and metabolism. Based on the obtained results, we can conclude that CsA in therapeutic concentration changes the expression profile of CYPs in human dermal fibroblasts, especially affecting genes linked to steroids synthesis and/or metabolism. It shows the potential mechanism of action of CsA in human dermal fibroblast cells.
Highlights
Cyclosporin A (CsA) is a classic immunosuppressive drug used, to prevent organ or tissue rejection, and in many immunologically-mediated diseases, for example, atopic dermatitis, pyoderma gangrenosum, pemphigus, psoriasis, rheumatoid arthritis and dry eye [1,2,3]
CsA is metabolized by cytochrome P450 (CYP), mainly by the isoform CYP3A4; it works as an inhibitor of 3A4, 2C19 and 2D6 in human liver microsomes [5]
For the microarray experiment. the chosen amount was a therapeutic concentration of CsA (100 ng mL−1 ), which occurs in the circulating blood of treated patients [18,19,20]
Summary
Cyclosporin A (CsA) is a classic immunosuppressive drug used, to prevent organ or tissue rejection, and in many immunologically-mediated diseases, for example, atopic dermatitis, pyoderma gangrenosum, pemphigus, psoriasis, rheumatoid arthritis and dry eye [1,2,3]. CsA is metabolized by cytochrome P450 (CYP), mainly by the isoform CYP3A4; it works as an inhibitor of 3A4, 2C19 and 2D6 in human liver microsomes [5]. Cytochrome P450 is a large, multifunctional superfamily of 57 genes encoding monooxygenases, which catalyze the conversion of many endobiotics and xenobiotics and have a strong clinical significance [6]. It produces chemicals essential for homeostasis, as well as bile acids, cholesterol, steroids, lipids, vitamin D, retinoids, and biogenic amines. CYPs are involved in the metabolism of most drugs, chemicals and environmental pollutants, as well as endogenous substances [6,7].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
