Changes in Steroids, Xenobiotics, and Drug‐Metabolism in Humans by Genetic Variations in NADPH Cytochrome P450 Oxidoreductase

A broad spectrum of human diseases, including disordered steroid metabolism, are caused by mutations in the NADPH cytochrome P450 oxidoreductase (POR) [1, 2]. 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 [2]. Cytochrome P450 proteins perform an extensive range of reactions, including the metabolism of steroids, drugs, and other xenobiotics. Therefore, genetic variations in POR change several metabolic pathways by changing the activities cytochromes P450 [2]. 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 [3, 4]. Recently, we have characterized POR variations from non‐clinical samples [5]. By analyzing the POR sequences from the 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 [6, 7]. Identification of severe effects of POR mutations on both the drug and the steroid metabolizing cytochromes P450 indicates that likely pathogenic mutations may be found in non‐clinical population. Their combination as compound heterozygotes or homozygous may severely impact both steroid and drug metabolism by modifications of cytochrome P450 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. Support or Funding Information Supported by grants from the Swiss National Science Foundation (31003A‐134926) & Novartis Foundation for Medical‐Biological Research (18A053) to AVP.References 1 Flück , C.E. and A.V. Pandey , Human P450 Oxidoreductase Deficiency , in Encyclopedia of Endocrine Diseases (Second Edition) , I. Huhtaniemi and L. Martini , Editors. 2019 , Academic Press : Oxford . p. 431 – 443 . 2 Pandey , A.V. and C.E. Flück , NADPH P450 oxidoreductase: structure, function, and pathology of diseases . Pharmacol Ther , 2013 . 138 ( 2 ): p. 229 – 54 . 3 Pandey , A.V. and P. Sproll , Pharmacogenomics of human P450 oxidoreductase . Front Pharmacol , 2014 . 5 : p. 103 . 4 Flück , C.E. , et al., Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome . Nat Genet , 2004 . 36 ( 3 ): p. 228 – 230 . 5 Burkhard , F.Z. , et al., P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms . J Steroid Biochem Mol Biol , 2017 . 165 : p. 38 – 50 . 6 Velazquez , M.N.R. , et al., Variability in human drug metabolizing cytochrome P450 CYP2C9, CYP2C19 and CYP3A5 activities caused by genetic variations in cytochrome P450 oxidoreductase . Biochem Biophys Res Commun , 2019 . 515 ( 1 ): p. 133 – 138 . 7 Parween , S. , et al., Variability in Loss of Multiple Enzyme Activities Due to the Human Genetic Variation P284T Located in the Flexible Hinge Region of NADPH Cytochrome P450 Oxidoreductase . Frontiers in Pharmacology , 2019 . 10 ( 1187 ).