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Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
In mammals, cholesterol is the common precursor of all steroid hormones, and its conversion to pregnenolone is the initial and rate-limiting step in hormone biosynthesis in steroidogenic tissues such as gonads and adrenal glands (Norlin and Wikvall 2007; Pikuleva 2006). The production of glucocorticoids and mineralocorticoids occurs in the adrenal gland and the final steps are catalyzed by three mitochondrial CYPs, namely, CYP11A1 (cholesterol side-chain cleavage enzyme), 11B1 (steroid 11β-hydroxylase), and 11B2 (aldosterone synthase, steroid 11(3/18-hydroxylase) (Maezawa et al. 2010; Miyakawa et al. 2000; Petrunak et al. 2014). The CYP11 members are important enzymes that participate in steroid biosynthesis and metabolism (Maezawa et al. 2010). CYP11B1 shows close homology to the CYP11B2 gene, which encodes aldosterone synthase and is normally expressed only in the zona glomerulosa. Both CYP11B genes map to chromosome 8q21, while CYP11A1 is located on chromosome 15q24.1 (Morohashi et al. 1987).
Adjuvant Treatment of Pituitary Disease
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
In practical terms metyrapone, a steroid 11β-hydroxylase inhibitor that has been available in Europe for the last 50 years (500 mg–4g daily in divided doses) is a reliable, reversible inhibitor of adrenal cortisol synthesis and secretion. It is sometimes used to improve overall metabolic and tissue status prior to transsphenoidal surgery or occasionally to help determine whether more invasive treatment of mild hypercortisolaemia is likely to yield symptomatic benefit. Metyrapone is also exploited as an interim adjunctive therapy while waiting for pituitary radiotherapy to reduce corticotroph function or as sole treatment in the longer term if patients are unable or unwilling to tolerate surgery, as its effects are not subject to tachyphylaxis. The drug should not be used in pregnancy or during lactation, but otherwise significant side effects are few, other than gastrointestinal upset and mild hirsutism.50 Even if hypocortisolaemia is avoided, the effects of a rapid fall in circulating cortisol levels to within normal limits may for some patients result in depressed mood, arthralgia and in the slightly longer term by disappointment that weight loss is not sustained and that dyslipidaemia, hypertension and impaired glucose tolerance may continue to need specific treatment. Failure of the phenotype to completely regress even after full biochemical remission contributes to a significantly reduced quality of life in the long term and demoralizing recognition that, despite biochemical remission, the perceived pre-morbid ‘self’ may be very slow to re-emerge.
Long-term follow-up of a female patient with non-classical 11β-hydroxylase deficiency and two novel mutations in CYP11B1
Published in Gynecological Endocrinology, 2019
Sabina Zacharieva, Ralitsa Robeva, Silvia Andonova, Radoslava Vazharova, Lubomir Balabanski, Maya Atanasoska, Draga Toncheva, Atanaska Elenkova, Alexey Savov
Compound heterozygosity due to two variants of the CYP11B1 gene (steroid 11β-hydroxylase gene, OMIM 610613) was established with NGS: NM_000497.3:c.946G>A (p.Val316Met) and NM_000497.3:c.1438delG (p.Asp480ThrfsTer2). Both mutations have not been previously reported as pathogenic in the literature. Sanger sequencing analysis of CYP11B1 exons 5 and 9 in patient and her mother revealed the maternal origin of the frameshift mutation c.1438delG (p.Asp480ThrfsTer2) (Figure 1). The patient’s daughter was also a heterozygous carrier of the same mutation. The father and the possibly affected brother of the patient have not been tested and their results are not available. The novel single nucleotide deletion found in exon 9 (c.1438delG) is predicted to result in a frameshift, introducing a premature termination 2 codons downstream of the deletion and loss of the terminal 23 amino acids. The shortening of the protein could cause functional changes, thus, this variant might be considered pathogenic. The second variant identified was c.946G>A. This substitution was observed as heterozygous in two Europeans among 60700 investigated individuals [The Exome Aggregation Consortium (ExAC) database; http://exac.broadinstitute.org/variant/8-143957665-C-T] and is not reported in other populations. By use of a pathogenicity-prediction algorithm (software PolyPhen-2, http://genetics.bwh.harvard.edu/pph2/) the variant was estimated as possibly damaging with a score of 1.000. Thus, the compound heterozygous status of both probably pathogenic CYP11B1 variants corresponds to the clinical picture of the patient. No pathogenic or probably pathogenic variants have been found in the other CAH related genes of the patient, such as CYP21A2, STAR, CYP17A1, HSD3B2, POR, CYP11A1, CYP11B2, or DHCR7.
Drug design strategies for Cushing’s syndrome
Published in Expert Opinion on Drug Discovery, 2019
S. A. Usanov, A. V. Kliuchenovich, N. V. Strushkevich
As evident from steroid biosynthesis and signaling, there are two major molecular targets for medical treatment of CS: the glucocorticoid receptor (GR) and the steroid-11β-hydroxylase (CYP11B1). Amongst the potential molecular targets for the treatment of chronic hypercortisolism, are intracellular transporters of cortisol while glucocorticoid precursors could also be considered. However, the identification and structure-function studies, with the subsequent validation studies of these proteins, remain elusive as of now.