Efonidipine, a Ca2+-Channel Blocker, Enhances the Production of Dehydroepiandrosterone Sulfate in NCI-H295R Human Adrenocortical Carcinoma Cells

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  • Ikeda Keiichi
    Department of Molecular and Cellular Biology, Institute of DNA Medicine, Research Center for Medical Sciences, The Jikei University School of Medicine
  • Saito Takatoshi
    Division of Diabetes and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine
  • Tojo Katsuyoshi
    Division of Diabetes and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine

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Steroid biosynthesis is initiated with transportation of cholesterol along with steroidogenic acute regulatory protein (StAR) into the mitchondria and is achieved with several steroidogenic enzymes. It has been reported that Ca2+ channel blockers (CCBs), such as azelnidipine, efonidipine and nifedipine, suppress the biosynthesis of aldosterone and cortisol, but the overall effects of CCBs on steroid biosynthesis remain to be clarified. The present study was designed to evaluate the effects of CCBs on the expression of steroidogenic enzymes and the production of adrenal androgen, dehydroepiandrosterone sulfate (DHEA-S) that has anti-atherosclerotic actions. NCI-H295R human adrenocortical carcinoma cells and HepG2 human hepatoma cells were cultured for 24 hours with or without a CCB (amlodipine, efonidipine, nifedipine, azelnidipine R(−)-efonidipine, verapamil or diltiazem). HepG2 hepatoma cells were used to confirm the effects of CCBs on the expression of StAR. In fact, efonidipine and nifedipine increased the expression of StAR in HepG2 cells. Efonidipine and nifedipine, but not other examined CCBs, also increased the N6, 2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP)-induced StAR mRNA, which reflects the action of adrenocorticotropic hormone, and efonidipine and R(−)-efonidipine enhanced the dbcAMP-induced DHEA-S production in NCI-H295R adrenocortical carcinoma cells. Therefore, efonidipine and nifedipine might increase the expression of StAR and, in turn, efonidipine enhanced the dbcAMP-induced DHEA-S production, independent of Ca2+ channel blockade. These results indicate that such effects are not associated with Ca2+ influx. Moreover, only efonidipine enhanced the angiotensin II-induced expression of StAR mRNA (P < 0.01 vs. angiotensin II alone). In conclusion, efonidipine might exert an additional action beyond anti-hypertensive actions.

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