title: 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 b5also 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: Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine and Department of Pharmacology, University of Michigan, Rm. 5560A MSRBII, 1150 W Medical Center Drive, Ann Arbor, MI 48109, United States. Electronic address: rauchus@med.umich.edu.
authors: Richard J
authors: RJ
authors: Auchus
mesh_terms: D000069501:Abiraterone Acetate / Q000737:chemistry; D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D003345:Corticosterone / Q000737:chemistry; D015786:Cytochromes b5 / Q000235:genetics; D003900:Desoxycorticosterone / Q000737:chemistry; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000378:metabolism; D006062:Gonadotropins / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D007021:Hypospadias / Q000601:surgery; D007246:Infertility / Q000235:genetics; D008297:Male; D008901:Mineralocorticoids / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D010084:Oxidation-Reduction; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000235:genetics
chemical_list: D000959:Antihypertensive Agents; C000594834:CYB5A protein, human; D005938:Glucocorticoids; D006062:Gonadotropins; D008901:Mineralocorticoids; D003900:Desoxycorticosterone; D015786:Cytochromes b5; D013255:Steroid 21-Hydroxylase; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D000069501:Abiraterone Acetate; D003345:Corticosterone
keywords: 17-Hydroxylase/17,20-lyase; 46XY DSD; Androgen; Hypertension; Infertility; Mineralocorticoid; Primary amenorrhea