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Cited by 88Pharmacogenetics and Drug MetabolismSexual Differentiation and DisordersAdrenal Hormones and Disorders

Consequences of POR mutations and polymorphisms

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Miller, Walter L., Agrawal, Vishal, Sandee, Duanpen, Tee, Meng Kian, Huang, Ningwu, Choi, Ji Ha, Morrissey, Kari, Giacomini, Kathleen M.·2011·Molecular and Cellular Endocrinology
DOI 10.1016/j.mce.2010.10.022PMC PMC4632974
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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.

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Cited by

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Authors
Miller, W. L., Agrawal, V., Sandee, D., Tee, M. K., Huang, N., Choi, J. H., Morrissey, K., & Giacomini, K. M.
Affiliations
University of California, San Francisco (US)
Corresponding author
Miller, Walter L.
ORCID
Venue
Molecular and Cellular Endocrinology
Publisher
Elsevier BV
Published
2011-04
Volume
336
Issue
1-2
Pages
174-179
ISSN
0303-7207 (ISSN-L)
DOI
10.1016/j.mce.2010.10.022
PMC
PMC4632974
OpenAlex
W2071072708
Cited by
88
References
23
Citations by year
2026: 1 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 3 · 2019: 7 · 2018: 6 · 2017: 5 · 2016: 8 · 2015: 4 · 2014: 6 · 2013: 13 · 2012: 8
FWCI
8.07
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Molecular and Cellular Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (R01 GM073020)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
cytochrome P450 oxidoreductase, Antley-Bixler syndrome, P450c17, steroidogenesis, CYP1A2, CYP2C19, CYP3A4, drug metabolism, promoter polymorphism, genetic variation, microsomal electron transport
MeSH terms
Congenital Abnormalities, Humans, Mutation, NADPH-Ferrihemoprotein Reductase, Pharmacogenetics, Polymorphism, Genetic, Promoter Regions, Genetic, Disorders of Sex Development, Transcription, Genetic

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