ArticleFrontiers in pharmacology2017
Altered CYP19A1 and CYP3A4 Activities Due to Mutations A115V, T142A, Q153R and P284L in the Human P450 Oxidoreductase.
Article in Frontiers in pharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 37 citations in OpenAlex.
- Deciphering cytochrome P450 reductase role in MASLD: molecular mechanisms and pathophysiological implications.Nature reviews. Gastroenterology & hepatology · 2026Review
- Structural context of NADPH-cytochrome P450 reductase mutations that alter cytochrome P450 1A2 substrate regioselectivity.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- A Novel POR G88S Mutation Causes Severe PORD and Establishes a Critical Pharmacogenomic Risk Profile.The Journal of clinical endocrinology and metabolism · 2026Article
- CYP19A1 regulates chemoresistance in colorectal cancer through modulation of estrogen biosynthesis and mitochondrial function.Cancer & metabolism · 2024Article
- Article
- Exploring Novel Variants of the Cytochrome P450 Reductase Gene (Biomolecules · 2023Article
- Single Mutations in Cytochrome P450 Oxidoreductase Can Alter the Specificity of Human Cytochrome P450 1A2-Mediated Caffeine Metabolism.Biomolecules · 2023Article
- Loss of Protein Stability and Function Caused by P228L Variation in NADPH-Cytochrome P450 Reductase Linked to Lower Testosterone Levels.International journal of molecular sciences · 2022Article
- Synthesis and Structure-Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents.Biomolecules · 2022Article
- The Central Role of Cytochrome P450 in Xenobiotic Metabolism-A Brief Review on a Fascinating Enzyme Family.Journal of xenobiotics · 2021Review
- Finding New Molecular Targets of Familiar Natural Products Using In Silico Target Prediction.International journal of molecular sciences · 2020Article
- Interaction Modes of Microsomal Cytochrome P450s with Its Reductase and the Role of Substrate Binding.International journal of molecular sciences · 2020Article
- NovelJournal of the Endocrine Society · 2020Article
- High-resolution QTL mapping in Tetranychus urticae reveals acaricide-specific responses and common target-site resistance after selection by different METI-I acaricides.Insect biochemistry and molecular biology · 2019Article
- 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 · 2019Article
- NADPH-cytochrome P450 reductase expression and enzymatic activity in primary-like human hepatocytes and HepG2 cells for in vitro biotransformation studies.Clinical hemorheology and microcirculation · 2019Article
- Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency.Pharmaceuticals (Basel, Switzerland) · 2018Article
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
All cytochromes P450s in the endoplasmic reticulum rely on P450 oxidoreductase (POR) for their catalytic activities. Mutations in POR cause metabolic disorders of steroid hormone biosynthesis and affect certain drug metabolizing P450 activities. We studied mutations A115V, T142A, Q153R identified in the flavin mononucleotide (FMN) binding domain of POR that interacts with partner proteins and P284L located in the hinge region that is required for flexibility and domain movements in POR. Human wild-type (WT) and mutant POR as well as CYP3A4 and CYP19A1 proteins in recombinant form were expressed in bacteria, and purified proteins were reconstituted in liposomes for enzyme kinetic assays. Quality of POR protein was checked by cytochrome c reduction assay as well as flavin content measurements. We found that proteins carrying mutations A115V, T142A located close to the FMN binding site had reduced flavin content compared to WT POR and lost almost all activity to metabolize androstenedione via CYP19A1 and showed reduced CYP3A4 activity. The variant P284L identified from apparently normal subjects also had severe loss of both CYP19A1 and CYP3A4 activities, indicating this to be a potentially disease causing mutation. The mutation Q153R initially identified in a patient with disordered steroidogenesis showed remarkably increased activities of both CYP19A1 and CYP3A4 without any significant change in flavin content, indicating improved protein-protein interactions between POR Q153R and some P450 proteins. These results indicate that effects of mutations on activities of individual cytochromes P450 can be variable and a detailed analysis of each variant with different partner proteins is necessary to accurately determine the genotype-phenotype correlations of POR variants.
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