Consequences of POR mutations and polymorphisms

Walter L. Miller, Vishal Agrawal, Duanpen Sandee, Meng Kian Tee, Ningwu Huang, Ji Ha Choi, Kari Morrissey, Kathleen M. Giacomini

Research output: Contribution to journalReview articlepeer-review

64 Scopus citations

Abstract

P450 oxidoreductase (POR) transports electrons from NADPH to all microsomal cytochrome P450 enzymes, including steroidogenic P450c17, P450c21 and P450aro. Severe POR mutations A287P (in Europeans) and R457H (in Japanese) cause the Antley-Bixler skeletal malformation syndrome (ABS) plus impaired steroidogenesis (causing genital anomalies), but the basis of ABS is unclear. We have characterized the activities of ∼40 POR variants, showing that assays based on P450c17 activities, but not cytochrome c assays, correlate with the clinical phenotype. The human POR gene is highly polymorphic: the A503V sequence variant, which decreases P450c17 activities to ∼60%, is found on ∼28% of human alleles. A promoter polymorphism (∼8% of Asians and ∼13% of Caucasians) at -152 reduces transcriptional activity by half. Screening of 35 POR variants showed that most mutants lacking activity with P450c17 or cytochrome c also lacked activity to support CYP1A2 and CYP2C19 metabolism of EOMCC (a fluorogenic non-drug substrate), although there were some remarkable differences: Q153R causes ABS and has ∼30% of wild-type activity with P450c17 but had 144% of WT activity with CYP1A2 and 284% with CYP2C19. The effects of POR variants on CYP3A4, which metabolizes nearly 50% of clinically used drugs, was examined with multiple, clinically relevant drug substrates, showing that A287P and R457H dramatically reduce drug metabolism, and that A503V variably impairs drug metabolism. The degree of activity can vary with the drug substrate assayed, as the drugs can influence the conformation of the P450. POR is probably an important contributor to genetic variation in both steroidogenesis and drug metabolism.

Original languageEnglish
Pages (from-to)174-179
Number of pages6
JournalMolecular and Cellular Endocrinology
Volume336
Issue number1-2
DOIs
StatePublished - 10 Apr 2011

Keywords

  • CYP2D6
  • CYP3A4
  • Cytochrome P450
  • Drug metabolism
  • Enzyme kinetics
  • P450 oxidoreductase
  • Pharmacogenetics
  • Steroidogenesis

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