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Testosterone, cytochrome P450, and cardiac hypertrophy
Author(s) -
Thum Thomas,
Borlak Jürgen
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0138com
Subject(s) - endocrinology , medicine , testosterone (patch) , dihydrotestosterone , cytochrome p450 , oxygenase , aromatase , androgen , androgen receptor , finasteride , biology , chemistry , metabolism , hormone , enzyme , biochemistry , prostate , prostate cancer , cancer , breast cancer
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, T., Borlak, J. Testosterone, cytochrome P450, and cardiac hypertrophy. FASEB J . 16, 1537–1549 (2002)