Altered CYP19A1 and CYP3A4 Activities Due to Mutations in the Flavin Mononucleotide Binding Domain of Human P450 Oxidoreductase

Abstract Cytochromes P450 proteins are responsible for the metabolism of many steroid hormones as well as drugs and xenobiotics. All cytochromes P450s in the endoplasmic reticulum rely on P450 oxidoreductase (POR) for their catalytic activities. Previously we and others have shown that mutations in POR cause metabolic disorders of steroid hormone biosynthesis and also affect certain drug metabolizing P450 activities. Human POR has distinct subdomains, which bind flavin molecules and interact with redox partners. We studied the mutations identified in flavin mononucleotide (FMN) binding domain of POR that interacts with partner proteins. We found that mutations A115V, T142A located close to the FMN binding site had reduced flavin content compared to wild type POR and lost almost all activity to metabolize androstenedione via CYP19A1 and also showed reduced CYP3A4 acitivies.