Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D02011 (FAD)
 5,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CYP11B1 and the closely related CYP11B2 are involved in the production of adrenal steroid hormones. Although in human their primary structure is 93% identical they are involved in the biosynthesis of functionally diverse products, such as glucocorticoids and mineralocorticoids, respectively. In contrast, bovine CYP11B1 combines both activities in one single enzyme. The CYP11B family belongs to class I cytochromes P450 that have been described in bacteria and mitochondria and receive their electrons from a low molecular weight iron sulphur protein which is reduced by a NADPH-dependent FAD-containing reductase. In this review, we summarise the current knowledge on the modulation of aldosterone and cortisol synthesis by transcriptional regulation, on the molecular level as consequence of mutations found in patients suffering from steroid hormone-related diseases as well as introduced by site-directed mutagenesis and as consequence of protein-protein interaction with both CYP11A1 and the natural redox partner adrenodoxin.
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PMID:Modulation of aldosterone and cortisol synthesis on the molecular level. 1502 88

Aldosterone synthase (CYP11B2) inhibitors (ASIs) represent an attractive therapeutic approach for mitigating the untoward effects of aldosterone. We characterized the pharmacokinetic/pharmacodynamic relationships of a prototypical ASI, (+)-(5R)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl]benzonitrile hydrochloride (CGS020286A, FAD286, FAD) and compared these profiles to those of the 11beta-hydroxylase inhibitor metyrapone (MET) in two rodent models of secondary hyperaldosteronism and corticosteronism. In chronically cannulated Sprague-Dawley rats, angiotensin II (ANG II) (300 ng/kg bolus + 100 ng/kg/min infusion) or adrenocorticotropin (100 ng/kg + 30 ng/kg/min) acutely elevated plasma aldosterone concentration (PAC) from approximately 0.26 nM to a sustained level of approximately 2.5 nM for 9 h. Adrenocorticotropin but not ANG II elicited a sustained increase in plasma corticosterone concentration (PCC) from approximately 300 to approximately 1340 nM. After 1 h of Ang II or adrenocorticotropin infusion, FAD (0.01-100 mg/kg p.o.) or MET (0.1-300 mg/kg p.o.) dose- and drug plasma concentration-dependently reduced the elevated PACs over the ensuing 8 h. FAD was approximately 12 times more dose-potent than MET in reducing PAC but of similar or slightly greater potency on a plasma drug concentration basis. Both agents also decreased PCC in the adrenocorticotropin model at relatively higher doses and with similar dose potencies, whereas FAD was 6-fold weaker based on drug exposures. FAD was approximately 50-fold selective for reducing PAC versus PCC, whereas MET was only approximately 3-fold selective. We conclude that FAD is a potent, orally active, and relatively selective ASI in two rat models of hyperaldosteronism. MET is an order of magnitude less selective than FAD but is, nevertheless, more potent as an ASI than as an 11beta-hydroxylase inhibitor.
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PMID:Pharmacodynamic and pharmacokinetic characterization of the aldosterone synthase inhibitor FAD286 in two rodent models of hyperaldosteronism: comparison with the 11beta-hydroxylase inhibitor metyrapone. 2035 76