Chrysin, a natural flavonoid enhances steroidogenesis and steroidogenic acute regulatory protein gene expression in mouse Leydig cells.
During the aging process of males, testosterone biosynthesis declines in testicular Leydig cells resulting in decreases in various physiological functions. To explore the possibility of delaying the decline using food supplements, we have studied steroidogenic effects of a natural flavonoid, chrysin, in mouse Leydig cells. Chrysin dramatically increased cyclic AMP (cAMP)-induced steroidogenesis in MA-10 mouse Leydig tumor cells. This result was confirmed using Leydig cells isolated from mouse testes. The steroidogenic effect of chrysin is not associated with an increase in expression of the P450 side-chain cleavage enzyme, required for the conversion of cholesterol to pregnenolone. In addition, when 22(R)hydroxylcholesterol was used as a substrate, chrysin induced a non-significant increase in steroid hormone, suggesting that the majority of the observed increase in steroidogenesis was due to the increased supply of substrate cholesterol. These observations were corroborated by showing that chrysin induced a marked increase in the expression of steroidogenic acute regulatory (StAR) protein, the factor that controls mitochondrial cholesterol transfer. Also, chrysin significantly increased StAR promoter activity and StAR mRNA level. Further studies indicated that this compound depressed expression of DAX-1, a repressor in StAR gene transcription. In the absence of cAMP, chrysin did not increase steroidogenesis. However, when a sub-threshold level of cAMP was used, StAR protein and steroid hormone were increased by chrysin to the levels seen with maximal stimulation of cAMP. These results suggest that while chrysin itself is unable to induce StAR gene expression and steroidogenesis, it appears to function by increasing the sensitivity of Leydig cells to cAMP stimulation.
Jana
Kuladip
K
Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
Yin
Xiangling
X
Schiffer
Randolph B
RB
Chen
Jau-Jiin
JJ
Pandey
Akhilesh K
AK
Stocco
Douglas M
DM
Grammas
Paula
P
Wang
Xingjia
X
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D008084:Lipoxygenase / Q000502:physiology; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics*; D011374:Progesterone / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction; D013739:Testosterone / Q000096:biosynthesis*; D000098682:Steroidogenic Acute Regulatory Protein
D052246:Cyclooxygenase 2 Inhibitors; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D005419:Flavonoids; C539966:Nr0b1 protein, mouse; D010750:Phosphoproteins; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000098682:Steroidogenic Acute Regulatory Protein; C043561:chrysin; D013739:Testosterone; D011374:Progesterone; D003994:Bucladesine; D008084:Lipoxygenase; D017868:Cyclic AMP-Dependent Protein Kinases