Development of test systems for the discovery of selective human aldosterone synthase (CYP11B2) and 11β-hydroxylase (CYP11B1) inhibitors. Discovery of a new lead compound for the therapy of congestive heart failure, myocardial fibrosis and hypertension

Molecular and Cellular Endocrinology

Volumn 217, Issue 1-2, 2004, Pages 249-254

  Bureik, Matthias ^a   Hübel, Katja ^a,b   Dragan, Calin Aurel ^a   Scher, Jochen ^a   Becker, Hans ^a   Lenz, Natalie ^a   Bernhardt, Rita ^a  

^a SAARLAND UNIVERSITY   (Germany)

^b MAX PLANCK INSTITUTE FOR BIOPHYSICAL CHEMISTRY   (Germany)

Author keywords

Aldosterone; Cortisol; CYP11B1; CYP11B2; Inhibitor screening

Indexed keywords

11BETA HYDROXYLASE INHIBITOR; ALDOSTERONE SYNTHASE; ALDOSTERONE SYNTHASE INHIBITOR; CARDIOVASCULAR AGENT; CLOTRIMAZOLE; ENZYME INHIBITOR; FLUCONAZOLE; KETOCONAZOLE; METYRAPONE; MICONAZOLE; MITOCHONDRIAL ENZYME; STEROID 11BETA MONOOXYGENASE; UNCLASSIFIED DRUG;

ANIMAL CELL CULTURE; ANTIHYPERTENSIVE ACTIVITY; CARDIOVASCULAR RISK; CONFERENCE PAPER; CONGESTIVE HEART FAILURE; DISEASE ASSOCIATION; DRUG ACTIVITY; DRUG EFFECT; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG INDICATION; DRUG MECHANISM; ENZYME ACTIVITY; ENZYME INHIBITION; FUNGAL STRAIN; HEART MUSCLE FIBROSIS; HORMONE ACTION; HORMONE SYNTHESIS; HYPERTENSION; MAMMAL CELL; MORTALITY; NONHUMAN; PATHOPHYSIOLOGY; PHARMACOLOGICAL BLOCKING; PRIORITY JOURNAL; SCHIZOSACCHAROMYCES POMBE; SCREENING TEST; STEROIDOGENESIS;

ALDOSTERONE SYNTHASE; CUSHING SYNDROME; DRUG EVALUATION, PRECLINICAL; ENDOMYOCARDIAL FIBROSIS; ENZYME INHIBITORS; HEART FAILURE, CONGESTIVE; HUMANS; HYPERTENSION; LEAD; RECOMBINANT PROTEINS; SCHIZOSACCHAROMYCES; STEROID 11-BETA-HYDROXYLASE; SUBSTRATE SPECIFICITY;

EID: 2342632561     PISSN: 03037207     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.mce.2003.10.027     Document Type: Conference Paper

References (14)

1. Alfa, C., Fantes, P., Hyams, J., Mcleod, M., Warbrick, E., 1993. Experiments with Fission Yeast. A Laboratory Course Manual. Cold Spring Harbor Press, Cold Spring Harbor, NY.
2. Belkina N.V., Lisurek M., Ivanov A.S., Bernhardt R. Modelling of three-dimensional structures of cytochromes P450 11B1 and 11B2. J. Inorg. Biochem. 87:2001;197-207
3. Bureik M., Lisurek M., Bernhardt R. The human steroid hydroxylases CYP11B1 and CYP11B2. Biol. Chem. 383:2002a;1537-1551
4. Bureik M., Schiffler B., Hiraoka Y., Vogel F., Bernhardt R. Functional expression of human mitochondrial CYP11B2 in fission yeast and identification of a new internal electron transfer protein, etp1. Biochemistry. 41:2002b;2311-2321
5. Bureik M., Zeeh A., Bernhardt R. Modulation of steroid hydroxylase activity in stably transfected V79MZh11B1 and V79MZh11B2 cells by PKC and PKD inhibitors. Endocr. Res. 28:2002c;351-355
6. Delyani J.A. Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology. Kidney Int. 57:2000;1408-1411
7. Denner, K., Bernhardt, R., 1998. Inhibition studies of steroid conversions mediated by human CYP11B1 and CYP11B2 expressed in cell cultures. In: Ishimura, K., Shimada, H., Suematsu, M. (Eds.), Oxygen Homeostasis and Its Dynamics. Springer, New York, pp. 231-236.
8. Denner K., Doehmer J., Bernhardt R. Cloning of CYP11B1 and CYP11B2 from normal human adrenal and their functional expression in COS-7 and V79 Chinese hamster cells. Endocr. Res. 21:1995a;443-448
9. Denner K., Vogel R., Schmalix W., Doehmer J., Bernhardt R. Cloning and stable expression of the human mitochondrial cytochrome P45011B1 cDNA in V79 Chinese hamster cells and their application for testing of potential inhibitors. Pharmacogenetics. 5:1995b;89-96
10. Ehmer P.B., Bureik M., Bernhardt R., Muller U., Hartmann R.W. Development of a test system for inhibitors of human aldosterone synthase (CYP11B2): screening in fission yeast and evaluation of selectivity in V79 cells. J. Steroid Biochem. Mol. Biol. 81:2002;173-179
11. Fisher A., Friel E.C., Bernhardt R., Gomez-Sanchez C., Connell J.M., Fraser R., Davies E. Effects of 18-hydroxylated steroids on corticosteroid production by human aldosterone synthase and 11beta-hydroxylase. J. Clin. Endocrinol. Metab. 86:2001;4326-4329
12. Maundrell K. nmt1 of fission yeast. A highly transcribed gene completely repressed by thiamine. J. Biol. Chem. 265:1990;10857-10864
13. Moreno S., Klar A., Nurse P. Molecular genetic analysis of fission yeast Schizosaccharomyces pombe. Meth. Enzymol. 194:1991;795-823
14. Pitt B., Zannad F., Remme W.J., Cody R., Castaigne A., Perez A., Palensky J., Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N. Engl. J. Med. 341:1999;709-717