title: Transcriptional regulation of human and murine short-chain dehydrogenase/reductases (SDRs) - an in silico approach.
abstract: Numerous physiological functions of the body are controlled by endogenous (e.g. steroids, retinoids, lipid mediators) or exogenous molecules (e.g. drugs, xenobiotics) that bind to transcription factors (TF). The biosynthesis and catabolism of these signaling molecules depend, apart from CYPs, on enzymes belonging to the short-chain dehydrogenase/reductase (SDR) superfamily. Moreover, the contribution of SDRs to the metabolism of therapeutic drugs and xenobiotics is increasingly recognized. However, only scarce information exists regarding the transcriptional regulation of most SDR proteins. This work aims to illustrate the role of nuclear receptors (NR) and TF related to oxidative stress, inflammation, hypoxia, and xenobiotics in the regulation of selected human and murine SDRs that play crucial roles in steroid, retinoid, eicosanoid, fatty acid, and xenobiotic metabolism. These include, for example, 17β-hydroxysteroid dehydrogenases, retinol dehydrogenases, and carbonyl reductases. Because existing experimental data are limited, an in silico analysis (TRANSFAC(®) Professional database) of the 5'-upstream sequences for putative response elements was performed. Experimental and in silico data suggest that pharmaceutical, environmental, or dietary NR ligands may alter SDR-mediated retinoid, steroid, and xenobiotic metabolism, likely affecting basic cellular events like energy expenditure, cell proliferation/differentiation, or aging processes. Also, some SDRs are possibly induced by their own substrates. Further experimental work is urgently needed to fully understand the NR-mediated transcriptional regulation of SDRs. This is essential for deducing their possible involvement in drug side effects and will help to identify new substrates and further physiological functions of these SDRs.
authors.affiliation: a Institute of Toxicology and Pharmacology for Natural Scientists , University Medical School Schleswig-Holstein , Kiel , Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Ebert
authors.affiliation: a Institute of Toxicology and Pharmacology for Natural Scientists , University Medical School Schleswig-Holstein , Kiel , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kisiela
authors.affiliation: a Institute of Toxicology and Pharmacology for Natural Scientists , University Medical School Schleswig-Holstein , Kiel , Germany.
authors.forename: Edmund
authors.initials: E
authors.lastname: Maser
mesh_terms: D000818:Animals; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D010088:Oxidoreductases / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012176:Retinoids / Q000493:pharmacokinetics; D013256:Steroids / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015262:Xenobiotics / Q000493:pharmacokinetics
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D012176:Retinoids; D013256:Steroids; D014157:Transcription Factors; D015262:Xenobiotics; D010088:Oxidoreductases
keywords: TRANSFAC database; Transcriptional regulation; carbonyl reductase; computational prediction of transcription factor binding sites; hydroxysteroid dehydrogenase; reductive Phase I metabolism; retinoid metabolism; retinol dehydrogenase; steroid metabolism; xenobiotic metabolism