ESPE Abstracts (2018) 89 FC14.3

Multisystem Endocrine Disorders

Regulation of Salt, Sugar and Sex Steroids in Humans by Genetic Variations in NADPH Cytochrome P450 Oxidoreductase (POR) Identified in 1000 Genome Samples

Amit V Pandey Ava,b, Sameer S Udhanea,b & Shaheena Parweena,b


aUniversity Children’s Hospital Bern, Bern, Switzerland; bDepartment of Biomedical Research, University of Bern, Bern, Switzerland

A broad spectrum of human diseases, including abnormalities in steroidogenesis, are caused by mutations in the NADPH cytochrome P450 oxidoreductase (POR) (1-4). Human POR is a diflavin reductase that transfers electrons from NADPH to small molecules, non-P450 redox partners and cytochrome P450 proteins in the endoplasmic reticulum. Cytochrome P450 proteins perform a very wide range of reactions, including metabolism of steroids, drugs and other xenobiotics. Therefore, genetic variations in POR can impact many different metabolic pathways by changing the activities of its redox partners like cytochromes P450 (1). Due to this unique role of POR in metabolism, it was believed for a long time that genetic defects in POR are unlikely, and indeed a POR knockout mouse is embryonically lethal. However, in 2004 the first human patients with defects in POR were reported, and since then over 200 different variations in POR have been found in patients and from large scale sequencing projects (4). Recently, we have turned our attention towards characterization of POR variations from non-clinical samples. By analyzing the POR sequences from 1000 genome and other sequencing projects, we identified potentially disease-causing variations and characterized these by functional studies using recombinant proteins produced in bacteria, yeast and mammalian cells. Identification of severe effects of POR mutations on both the drug and the steroid metabolizing cytochrome P450s, indicates that likely pathogenic mutations may be found in apparently normal (non-clinical) population. Their combination as compound heterozygotes or homozygous may lead to a severe impact on both steroid and drug metabolism by modification of POR redox partner activities. Variations in POR need to be evaluated individually. Changes in drug and steroid metabolism due to genetic variations can be addressed using personalized metabolic profiling and supplementation using modified dosages of drugs and steroids.

References: 1. Pandey AV & Flück CE. NADPH P450 oxidoreductase: structure, function, and pathology of diseases. Pharmacol Ther 2013 138 229–254.

2. Udhane SS et al. Altered CYP19A1 and CYP3A4 activities due to mutations A115V, T142A, Q153R and P284L in the human P450 oxidoreductase. Front Pharmacol 2017 8 580. doi: 10.3389/fphar.2017.00580.

3. Parween S et al. P450 Oxidoreductase deficiency: loss of activity caused by protein instability from a novel L374H mutation. J Clin Endocrinol Metab 2017 101 4789–4798.

4. Burkhard FZ et al. P450 oxidoreductase deficiency: analysis of mutations and polymorphisms. J Steroid Biochem Mol Biol. 2017 165 38–50.

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