Inhibitors of P450-dependent steroid biosynthesis: From research to medical treatment

Bossche, H. Vanden

doi:10.1016/0960-0760(92)90328-g

Cited by 85 publications

(9 citation statements)

References 126 publications

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“…CYP11A1 has been intensively studied during the last 40 years (reviewed in (Guengerich, 2005; Pikuleva, 2006; Miller et al, 2011)), yet little is currently known about the effect of marketed drugs on activity of CYP11A1, both in vivo and in vitro . Our knowledge in this area is mainly limited to earlier studies in the field showing that CYP11A1, as well as some other steroidogenic P450s, are inhibited by the antifungal agent ketoconazole and anticonvulsant aminoglutethimide (withdrawn from the US market in 1986), whose administration leads to adrenocortical dysfunction (Bossche, 1992; Harvey et al, 2003). Recently, we determined the crystal structure of CYP11A1 (Mast et al, 2011) and compared it to the structure of CYP46A1, another P450 which utilizes cholesterol as the endogenous substrate.…”

Section: Introductionmentioning

confidence: 99%

Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents

Mast

Linger

Pikuleva

2013

Molecular and Cellular Endocrinology

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In vertebrates, the biosynthesis of steroid hormones is initiated by cytochrome P450 CYP11A1 which converts cholesterol to pregnenolone. We investigated whether some of the experimental and FDA-approved therapeutic agents alter the activity of CYP11A1 in the reconstituted system in vitro. We found that under the experimental conditions used and when phospholipids are included, ketoconazole, posaconazole, carbenoxolone, and selegiline inhibit CYP11A1-mediated production of pregnenolone by at least 67%. Conversely, pemirolast, clobenpropit, desogestrel, dexmedetomidine, and tizanidine stimulate the enzyme activity by up to 70%. We then evaluated the identified inhibitors and activators for spectral binding to CYP11A1 and their effect on enzyme activity in the absence of phospholipids. The data obtained provide insight into how different drugs interact with CYP11A1 and demonstrate that P450 association with the lipid bilayer determines, in many cases, a drug’s effect on enzyme activity.

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Section: Introductionmentioning

confidence: 99%

Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents

Mast

Linger

Pikuleva

2013

Molecular and Cellular Endocrinology

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“…Aminoglutethimide (AG) was used as an anticonvulsant for several years before its adrenostatic activity was discovered. AG inhibits both P450 side‐chain cleavage (scc) enzyme and aromatase [1]. A number of studies have demonstrated the usefulness of AG (0á5–2 g day −1 ) in the treatment of patients with CS [2–5].…”

Section: Introductionmentioning

confidence: 99%

New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line

Fassnacht

Hahner

Beuschlein

et al. 2000

Eur J Clin Investigation

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Our data demonstrate that adrenostatic compounds not only act by suppression of steroidogenic enzymes but can also influence both ACTH-R expression and cell proliferation in adrenal cells. As these effects occur in vitro at concentrations that are reached during treatment with these drugs in patients, they are probably also of clinical relevance. Particularly the antiproliferative activity of ETO may be useful in Cushing's syndrome due to adrenocortical cancer. The interaction of steroidogenesis, ACTH-R and glucocorticoid receptor expression as well as cell proliferation provides a new concept of the intra-adrenal response to stress in humans.

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“…At concentrations >100 nM, ketoconazole inhibits both fungal and mammalian CYP51s, that play an important role in ergosterol and cholesterol biosynthesis respectively, and also affect the activity of enzymes involved in catabolism of cholesterol. More specifically, ketoconazole inhibits 17-hydroxylase-17,20-lyase (CYP17), the cholesterol side chain cleavage enzyme (CYP11A1), and the 11-β-hydroxylase (CYP11B1) (Vanden 1992). The 50% inhibitory concentration (IC 50 ) of ketoconazole for lanosterol synthase was elucidated to be 11.7 nM (Sakaeda et al 2005).…”

Section: Resultsmentioning

confidence: 99%

Homology modeling and docking studies on oxidosqualene cyclases associated with primary and secondary metabolism of Centella asiatica

Kumar

Gajula

et al. 2013

SpringerPlus

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Centella asiatica is a well-known medicinal plant, produces large amount of triterpenoid saponins, collectively known as centelloids, with a wide-spectrum of pharmacological applications. Various strategies have been developed for the production of plant secondary metabolites in cell and tissue cultures; one of these is modular metabolic engineering, in which one of the competitive metabolic pathways is selectively suppressed to channelize precursor molecules for the production of desired molecules by another route. In plants the precursor 2,3-oxidosqualene is shared in between two competitive pathways involved with two isoforms of oxidosqualene cyclases. One is primary metabolic route for the synthesis of phytosterol like cycloartenol by cycloartenol synthase; another is secondary metabolic route for the synthesis of triterpenoid like β-amyrin by β-amyrin synthase. The present work is envisaged to evaluate specific negative modulators for cycloartenol synthase, to channelize the precursor molecule for the production of triterpenoids. As there are no experimentally determined structures for these enzymes reported in the literature, we have modeled the protein structures and were docked with a panel of ligands. Of the various modulators tested, ketoconazole has been evaluated as the negative modulator of primary metabolism that inhibits cycloartenol synthase specifically, while showing no interaction with β-amyrin synthase. Amino acid substitution studies confirmed that, ketoconazole is specific modulator for cycloartenol synthase, LYS728 is the key amino acid for the interaction. Our present study is a novel approach for identifying a suitable specific positive modulator for the over production of desired triterpenoid secondary metabolites in the cell cultures of plants.

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Inhibitors of P450-dependent steroid biosynthesis: From research to medical treatment

Cited by 85 publications

References 126 publications

Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents

Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents

New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line

Homology modeling and docking studies on oxidosqualene cyclases associated with primary and secondary metabolism of Centella asiatica

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