Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic.

Abstract

Steroid 17-hydroxylase 17,20-lyase (cytochrome P450c17, P450 17A1, CYP17A1) catalyzes two major reactions: steroid 17-hydroxylation followed by the 17,20-lyase reactions. The most severe mutations in the cognate CYP17A1 gene abrogate all activities and cause combined 17-hydroxylase/17,20-lyase deficiency (17OHD), a biochemical phenotype that is replicated by treatment with the potent CYP17A1 inhibitor abiraterone acetate. The adrenals of patients with 17OHD synthesize 11-deoxycorticosterone (DOC) and corticosterone but no 19-carbon steroids, similar to the rodent adrenal, and DOC causes hypertension and hypokalemia. Loss of 17,20-lyase activity precludes sex steroid synthesis and leads to sexual infantilism. Rare missense CYP17A1 mutations minimally disrupt 17-hydroxylase activity but cause isolated 17,20-lyase deficiency (ILD), Mutations in the POR gene encoding the required cofactor protein cytochrome P450-oxidoreductase causes a spectrum of disease from ILD to 17OHD combined with 21-hydroxylase and aromatase deficiencies, sometimes including skeletal malformations. Mutations in the CYB5A gene encoding a second cofactor protein cytochrome b5 also selectively disrupt 17,20-lyase activity and cause the purest form of ILD. The clinical manifestations of these conditions are best understood in the context of the biochemistry of CYP17A1.

• Authors: Richard J Auchus
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 165 Issue Pt A Pg. 71-78 (01 2017) ISSN: 1879-1220 [Electronic] England
• PMID: 26862015 (Publication Type: Journal Article, Review, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Antihypertensive Agents
• CYB5A protein, human
• Glucocorticoids
• Gonadotropins
• Mineralocorticoids
• Desoxycorticosterone
• Cytochromes b5
• Steroid 21-Hydroxylase
• CYP17A1 protein, human
• Steroid 17-alpha-Hydroxylase
• Abiraterone Acetate
• Corticosterone

Topics

• Abiraterone Acetate (chemistry)
• Adrenal Hyperplasia, Congenital (drug therapy, genetics, metabolism)
• Animals
• Antihypertensive Agents (therapeutic use)
• Corticosterone (chemistry)
• Cytochromes b5 (genetics)
• Desoxycorticosterone (chemistry)
• Female
• Genotype
• Glucocorticoids (metabolism)
• Gonadotropins (metabolism)
• Humans
• Hypertension (metabolism)
• Hypospadias (surgery)
• Infertility (genetics)
• Male
• Mineralocorticoids (metabolism)
• Mutation
• Mutation, Missense
• Oxidation-Reduction
• Steroid 17-alpha-Hydroxylase (genetics, metabolism)
• Steroid 21-Hydroxylase (genetics)