Altered expression of cytochrome P450 enzymes involved in metabolism of androgens and vitamin D in the prostate as a ris
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REVIEW
Altered expression of cytochrome P450 enzymes involved in metabolism of androgens and vitamin D in the prostate as a risk factor for prostate cancer Oksana V. Maksymchuk1 · Vladimir I. Kashuba1,2 Received: 22 January 2020 / Revised: 2 July 2020 / Accepted: 9 July 2020 © Maj Institute of Pharmacology Polish Academy of Sciences 2020
Abstract Prostate cancer is the most common malignant disease among men. The signaling pathways, regulated by the androgen and vitamin D receptors, play a key role in prostate cancer. The intracellular level of androgens and vitamin D determines not only receptor functionality, but also the efficacy of cellular processes regulated by them (cell proliferation, apoptosis, differentiation etc.). It is known that several androgen-metabolizing P450s (CYP3A4/5/43 and CYP2B6) and P450 enzymes (CYP2R1, CYP27A1, CYP27B1, CYP24A1, CYP3A4, CYP2J2), which are necessary for vitamin D metabolism, are expressed in the prostate. It was shown that alterations in an expression pattern of the certain cytochrome P450s might lead to the development of castration-resistant cancer (CYP3A4, CYP2J2, CYP24A1), and to chemo-resistance (CYP3A4, CYP3A5, CYP2B6) and early mortality (CYP2B6, CYP27A1, CYP24A1). Moreover, steroidogenic CYPs (CYP17A1, CYP11A1) are not expressed in normal prostate tissue. Alterations in their expression levels in steroidogenic tissues are closely associated with carcinogenesis, and, most importantly, with the development of aggressive forms of prostate cancer. Hence, it is important, to study how expression of CYPs in the prostate might be regulated, to understand the mechanisms of disease development and to improve the effectiveness of therapy. Several CYPs (CYP3A43, CYP2B6, CYP27A1, CYP24A1) can be considered as prognostic and diagnostic markers of prostate cancer. To propose personalized treatment, individual differences in CYP expression should be taken into account. Keywords Androgens · Cytochrome P450 · Prostate cancer · Vitamin D
Introduction Cytochrome P450 is a superfamily of enzymes (P450s, CYPs) that catalyze hydroxylation of compounds, using molecular oxygen with the help of NADPH or NADH, which are a source of electrons. In general, cytochrome P450 is an oxidase with mixed functions. To date, up to 60 * Oksana V. Maksymchuk [email protected] Vladimir I. Kashuba [email protected] 1
Department of Molecular Oncogenetics, Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, 150, Zabolotnogo Street, Kyiv 03143, Ukraine
Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, 17177 Stockholm, Sweden
2
human genes encoding various individual cytochrome P450 enzymes were identified and described. The first nomenclature schema for cytochrome P450 enzymes was proposed by Nebert et al. in 1987, based on divergent evolution of the P450 enzymes and amino acid sequence similarity of the members of this superfamily [1]. Nelson et al. in 1993 first recommended using the italicized root
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