Testosterone, cytochrome P450, and cardiac hypertrophy.
Cytochrome P450 mono-oxygenases (CYP) play an essential role in steroid metabolism, and there is speculation that sex hormones might influence cardiac mass and physiology. As CYP mono-oxygenases activity is frequently altered during disease, we tested our hypothesis that CYP mono-oxygenase expression and testosterone metabolism are altered in cardiac hypertrophy. We investigate major CYP mono-oxygenase isoforms and other steroid-metabolizing enzymes and the androgen receptor in normal, hypertrophic, and assist device-supported human hearts and in spontaneously hypertensive rats (SHR). We show increased and idiosyncratic metabolism of testosterone in hypertrophic heart and link these changes to altered CYP mono-oxygenase expression. We show significant induction of 5-alpha steroid reductase and P450 aromatase gene expression and enhanced production of dihydrotestosterone, which can be inhibited by the 5-alpha reductase inhibitor finasteride. We show increased gene expression of the androgen receptor and increased levels of lipid peroxidation in diseased hearts, the latter being markedly inhibited by CYP mono-oxygenase inactivation. We show alpha-MHC to be significantly repressed in cardiac hypertrophy and restored to normal on testosterone supplementation. We conclude that heart-specific steroid metabolism is of critical importance in cardiac hypertrophy
Thum
Thomas
T
Center of Drug Research and Medical Biotechnology, Fraunhofer Institute of Toxicology and Aerosol Research, Hannover, Germany.
Borlak
Jürgen
J
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics; D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics; D012083:Renin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016755:Proto-Oncogene Proteins c-jun; D011944:Receptors, Androgen; D017392:Thiobarbituric Acid Reactive Substances; D013739:Testosterone; D018120:Finasteride; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D012083:Renin; D018995:Myosin Heavy Chains