Testosterone, cytochrome P450, and cardiac hypertrophy.

Abstract

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