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.

Keywords:

• Transcriptional regulation
• reductive Phase I metabolism
• computational prediction of transcription factor binding sites
• TRANSFAC database
• hydroxysteroid dehydrogenase
• retinol dehydrogenase
• carbonyl reductase
• xenobiotic metabolism
• steroid metabolism
• retinoid metabolism

Acknowledgements

We apologize to colleagues for citing reviews instead of original work due to space limitations.

Disclosure statement

The authors report no declarations of interest.

Funding information

This project was supported by grants from the Deutsche Forschungsgemeinschaft DFG (MA 1704/12-1).