CoChat
Sign Up
Cited by 78Sexual Differentiation and DisordersAdrenal Hormones and DisordersPharmacogenetics and Drug Metabolism

Differential Inhibition of CYP17A1 and CYP21A2 Activities by the P450 Oxidoreductase Mutant A287P

Open access
Dhir, Vivek, Ivison, Hannah E., Krone, Nils, Shackleton, Cedric H. L., Doherty, Aidan J., Stewart, Paul M., Arlt, Wiebke·2007·Molecular Endocrinology
DOI 10.1210/me.2007-0066
Open this paper in CoChat — free accountOpen PDF

Abstract

P450 oxidoreductase (POR) has a pivotal role in facilitating electron transfer from nicotinamide adenine dinucleotide phosphate to microsomal cytochrome P450 (CYP) enzymes, including the steroidogenic enzymes CYP17A1 and CYP21A2. Mutations in POR have been shown recently to cause congenital adrenal hyperplasia with apparent combined CYP17A1 and CYP21A2 deficiency that comprises a variable clinical phenotype, including glucocorticoid deficiency, ambiguous genitalia, and craniofacial malformations. To dissect structure-function relationships potentially explaining this phenotypic diversity, we investigated whether specific POR mutations have differential effects on CYP17A1 and CYP21A2. We compared the impact of missense mutations encoding for single amino acid changes in three distinct regions of the POR molecule: 1), Y181D and H628P close to the central electron transfer area, 2) S244C located within the hinge close to the flavin adenine dinucleotide and flavin mononucleotide domains of POR, and 3) A287P that is clearly distant from the two other regions. Functional analysis using a yeast microsomal assay with coexpression of human CYP17A1 or CYP21A2 with wild-type or mutant human POR revealed equivalent decreases in CYP17A1 and CYP21A2 activities by Y181D, H628P, and S244C. In contrast, A287P had a differential inhibitory effect, with decreased catalytic efficiency (Vmax/Km) for CYP17A1, whereas CYP21A2 retained near normal activity. In vivo analysis of urinary steroid excretion by gas chromatography/mass spectrometry in 11 patients with POR mutations showed that A287P homozygous patients had the highest corticosterone/cortisol metabolite ratios, further indicative of preferential inhibition of CYP17A1. These findings provide novel mechanistic insights into the redox regulation of human steroidogenesis. Differential interaction of POR with electron-accepting CYP enzymes may explain the phenotypic variability in POR deficiency, with additional implications for hepatic drug metabolism by POR-dependant CYP enzymes.

Integrity signals

Registry

Crossref · 10.1210/me.2007-0066

Cites

23 of 23 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In a previous study, patients with homozygous p.A287P had significantly increased corticosterone over cortisol metabolite ratios.

    “We have demonstrated this in a previous study by describing significantly increased corticosterone over cortisol metabolite ratios in patients with homozygous p.A287P (21).”

    From Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency (2012) · cites this paper as [21]

  • In vitro findings indicated a significantly higher impairment of 17α-hydroxylase over 21-hydroxylase for p.A287P.

    “These in vivo findings were entirely consistent with the in vitro findings that indicated a significantly higher impairment of 17α-hydroxylase over 21-hydroxylase for p.A287P (21).”

    From Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency (2012) · cites this paper as [21]

  • p.A287P causes predominant 17α-hydroxylase over 21-hydroxylase impairment.

    “We previously demonstrated predominant 17α-hydroxylase over 21-hydroxylase impairment by p.A287P (21), and indeed, arterial hypertension has been documented in homozygous carriers (3, 12), probably caused by excess deoxycorticosterone production as in classical 17α-hydroxylase deficiency.”

    From Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency (2012) · cites this paper as [21]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Dhir, V., Ivison, H. E., Krone, N., Shackleton, C. H. L., Doherty, A. J., Stewart, P. M., & Arlt, W.
Affiliations
  • University of Birmingham (GB)
  • University of Sussex (GB)
Corresponding author
Arlt, Wiebke
ORCID
Venue
Molecular Endocrinology
Publisher
The Endocrine Society
Published
2007-08-01
Volume
21
Issue
8
Pages
1958-1968
ISSN
  • 0888-8809 (ISSN-L)
  • 1944-9917
DOI
10.1210/me.2007-0066
OpenAlex
W2009818733
Cited by
78
References
23
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 1 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 3 · 2014: 1 · 2013: 5 · 2012: 7
FWCI
3.69
Type
journal article
Language
en
Open access
Locations
  • Molecular Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
cytochrome P450 oxidoreductase, CYP17A1, CYP21A2, congenital adrenal hyperplasia, steroidogenesis, electron transfer, flavin adenine dinucleotide, flavin mononucleotide, catalytic efficiency, phenotypic variability, hepatic drug metabolism
MeSH terms
Alanine, Amino Acid Sequence, Animals, Humans, Molecular Sequence Data, NADPH-Ferrihemoprotein Reductase, Proline, Rabbits, Steroid 17-alpha-Hydroxylase, Steroid 21-Hydroxylase, Amino Acid Substitution, Mice, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review