Enzyme-activated inhibitors of steroidal hydroxylases

Johnston, J.O'Neal; Wright, Carol; Holbert, Gene W.

doi:10.1016/0960-0760(94)00152-c

Cited by 23 publications

(15 citation statements)

References 54 publications

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“…Although the formation of a C 18 - gem- diol has been proposed by Johnston et al. [ 72 ], the precise mechanism of oxidation is still unknown. This proposed method of substrate stabilisation may explain the regioselectivity of the two CYP11B isoforms and can be attributed to the subtle changes observed on two sides of the active site cavity; the cavity near helix K and the positioning of helix B′.…”

Section: Resultsmentioning

confidence: 99%

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Roumen

Sanders

Pieterse

et al. 2007

J Comput Aided Mol Des

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Aldosterone is synthesised by aldosterone synthase (CYP11B2). CYP11B2 has a highly homologous isoform, steroid 11b-hydroxylase (CYP11B1), which is responsible for the biosynthesis of aldosterone precursors and glucocorticoids. To investigate aldosterone biosynthesis and facilitate the search for selective CYP11B2 inhibitors, we constructed three-dimensional models for CYP11B1 and CYP11B2 for both human and rat. The models were constructed based on the crystal structure of Pseudomonas Putida CYP101 and Oryctolagus Cuniculus CYP2C5. Small steric active site differences between the isoforms were found to be the most important determinants for the regioselective steroid synthesis. A possible explanation for these steric differences for the selective synthesis of aldosterone by CYP11B2 is presented. The activities of the known CYP11B inhibitors metyrapone, R-etomidate, R-fadrazole and S-fadrazole were determined using assays of V79MZ cells that express human CYP11B1 and CYP11B2, respectively. By investigating the inhibitors in the human CYP11B models using molecular docking and molecular dynamics simulations we were able to predict a similar trend in potency for the inhibitors as found in the in vitro assays. Importantly, based on the docking and dynamics simulations it is possible to understand the enantioselectivity of the human enzymes for the inhibitor fadrazole, the R-enantiomer being selective for CYP11B2 and the S-enantiomer being selective for CYP11B1.

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Section: Resultsmentioning

confidence: 99%

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Roumen

Sanders

Pieterse

et al. 2007

J Comput Aided Mol Des

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“…At present, such suggestions remain purely theoretical, but one piece of evidence shows that local corticosteroid production exerts a real physiological effect. 19‐Ethynyldeoxycorticosterone is an irreversible inactivator of aldosterone synthase 76 that, when administered to the Dahl SS/jr rat model of hypertension, causes a reduction in salt‐induced blood pressure. Administration of 5 ng/h 19‐ethynyldeoxycorticosterone via an i.c.v.…”

Section: Discussionmentioning

confidence: 99%

Extra‐adrenal production of corticosteroids

Davies

MacKenzie

2003

Clin Exp Pharma Physio

119

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SUMMARY1. The major corticosteroids aldosterone and cortisol (corticosterone in rodents) are secreted from the adrenal cortex under the regulation of the renin-angiotensin system and the hypothalamic-pituitary-adrenal axis.2. In addition to their accepted roles in such processes as blood pressure regulation, glycogenesis, hepatic glyconeogenesis and immunosuppression, the corticosteroids have been implicated in the development of cardiac fibrosis, modulation of hippocampal neuron excitability, memory formation and neurodegeneration.3. The advent of sensitive molecular biological techniques has produced a wealth of evidence to support the existence of extra-adrenal corticosteroidogenic systems. Most attention has been paid to the cardiovascular system and the central nervous system, where the full array of enzymes required for the de novo synthesis of corticosteroids from cholesterol has been identified. 4. Although the evidence for local corticosteroid production is strong, the quantities of steroid would be small compared with adrenal production. Therefore, it is still a matter of debate as to whether extra-adrenal corticosteroids are of any physiological significance. This will depend on factors such as local concentration, proximity to target cells and, possibly, to tissuespecific control mechanisms.

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“…30 Both the estrogen deprivation caused by the Gn-RH analogues and their direct effect may induce apoptosis in cells that survive chemotherapy. 31 Several studies have described that a subsequent pregnancy after breast carcinoma has no adverse effect on prognosis. 32 Indeed, this may contribute to the psychological well being of the young woman who has breast carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Gonadotropin‐releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma

Recchia

Saggio

Amiconi

et al. 2005

Cancer

120

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BACKGROUND The objective of the current study was a retrospective evaluation of 100 consecutive premenopausal women with high‐risk, early breast carcinoma who received a gonadotropin‐releasing hormone (Gn‐RH) analogue as ovarian protection during adjuvant chemotherapy. METHODS After surgery, patients received a Gn‐RH analogue and adjuvant chemotherapy, which was tailored to their peculiar biologic features. The median patient age was 43 years (range, 27–50 yrs). Fifty‐two women had positive estrogen receptor (ER) status, and 48 women had negative ER status. There were 64 women with Stage II breast carcinoma and 36 women with UICC Stage III breast carcinoma. All patients had their serum estradiol suppressed to values < 40 pg/mL. The chemotherapy regimens administered included cyclophosphamide, methotrexate, and 5‐fluorouracil (n = 26 patients) and anthracycline‐based regimens (n = 74 patients, including 9 patients who had > 10 positive axillary lymph nodes, who also received high‐dose chemotherapy with autologous peripheral blood progenitor cell transplantation). Patients with positive c‐erb‐2 status also received a taxane. Eighty patients received radiation therapy. During therapy with the Gn‐RH analogue, patients who had a positive ER status after chemotherapy received an aromatase inhibitor. RESULTS After a median follow‐up of 75 months, normal menses were resumed by all patients younger than age 40 years and by 56% of patients older than age 40 years. Three pregnancies were observed that resulted in two normal deliveries and one voluntary abortion. The projected recurrence‐free survival rates at 5 years and 10 years were 84% and 76%, respectively; and the projected overall survival rates at 5 years and 10 years were 96% and 91%, respectively. CONCLUSIONS The current data showed that, in premenopausal women with early breast carcinoma, the addition of a Gn‐RH analogue to adjuvant therapy and temporary total estrogen suppression in patients with ER‐positive disease was tolerated well, protected long‐term ovarian function, and appeared to improve the expected clinical outcome. Cancer 2006. © 2005 American Cancer Society.

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Enzyme-activated inhibitors of steroidal hydroxylases

Cited by 23 publications

References 54 publications

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Extra‐adrenal production of corticosteroids

Gonadotropin‐releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma

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