Dehydroepiandrosterone and Its CYP7B1 Metabolite 7α-Hydroxydehydroepiandrosterone Regulates 11β-Hydroxysteroid Dehydrogenase 1 Directions in Rat Leydig Cells

被引:4
作者
Zhu, Qiqi [1 ,2 ]
Dong, Yaoyao [2 ,3 ]
Li, Xiaoheng [1 ,2 ]
Ni, Chaobo [1 ,2 ]
Huang, Tongliang [1 ,2 ]
Sun, Jianliang [4 ]
Ge, Ren-Shan [1 ,2 ]
机构
[1] Wenzhou Med Univ, Dept Anesthesiol, Affiliated Hosp 2, Wenzhou, Peoples R China
[2] Wenzhou Med Univ, Yuying Childrens Hosp, Wenzhou, Peoples R China
[3] Wenzhou Med Univ, Dept Pharm, Affiliated Hosp 2, Wenzhou, Peoples R China
[4] Zhejiang Univ, Hangzhou Peoples Hosp 1, Dept Anesthesia, Hangzhou Hosp, Hangzhou, Peoples R China
来源
FRONTIERS IN ENDOCRINOLOGY | 2020年 / 10卷
关键词
steroids; dehydroepiandrosterone; 7; alpha-hydroxydehydroepiandrosterone; leydig cells; BETA-HYDROXYSTEROID DEHYDROGENASE; HEXOSE-6-PHOSPHATE DEHYDROGENASE; TISSUE DISTRIBUTION; HORMONE; TYPE-1; PATHWAY; CLONING; INTERCONVERSION; TESTOSTERONE; SYSTEM;
D O I
10.3389/fendo.2019.00886
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: The purpose of this study was to investigate cytochrome P450-7B1 (CYP7B1) in the human and rat testes to regulate 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1) activity. We hypothesized that dehydroepiandrosterone (DHEA) and its product 7 alpha-hydroxydehydroepiandrosterone (7 alpha OHD) after catalysis of CYP7B1 played a critical role in driving the direction of 11 beta-HSD1, because 7 alpha OHD is an alternative substrate for 11 beta-HSD1. Methods: We examined the influence of DHEA and 7 alpha OHD on 11 beta-HSD1 activities in both intact Leydig cells and microsomes using radioactive substrates and identified the location of CYP7B1 in Leydig cells using immunohistochemical staining, Western blot, and qPCR. Results: We found that DHEA stimulated 11 beta-HSD1 oxidase activity in intact cells (EC50 = 0.97 +/- 0.11 mu M) and inhibited its reductase activity (IC50 = 1.04 +/- 0.06 mu M). In microsomes, DHEA was a competitive inhibitor of the reductase activity. The 11 beta-HSD1 oxidase activity in intact cells was inhibited by 7 alpha OHD (IC50 = 1.18 +/- 0.12 mu M), and the reductase activity was enhanced (EC50 = 0.7 +/- 0.04 mu M). 7 alpha OHD was a competitive inhibitor of 11 beta-HSD1 oxidase. CYP7B1 was present in rat Leydig cells, as shown by immunohistochemistry, Western blotting, and qPCR analysis. Conclusion: Our results are consistent with a conclusion that DHEA in the circulation driving 11 beta-HSD1 toward an oxidase in Leydig cells mainly through inhibiting the reductase of the enzyme, while 7 alpha OHD (CYP7B1 catalytic product of DHEA) drives the enzyme toward the opposite direction.
引用
收藏
页数:10
相关论文
共 37 条
[1]  
AGARWAL AK, 1994, J BIOL CHEM, V269, P25959
[2]  
AGARWAL AK, 1989, J BIOL CHEM, V264, P18939
[3]   CLONING AND TISSUE DISTRIBUTION OF THE HUMAN 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-2 ENZYME [J].
ALBISTON, AL ;
OBEYESEKERE, VR ;
SMITH, RE ;
KROZOWSKI, ZS .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 1994, 105 (02) :R11-R17
[4]   Hexose-6-phosphate dehydrogenase determines the reaction direction of 11β-hydroxysteroid dehydrogenase type 1 as an oxoreductase [J].
Atanasov, AG ;
Nashev, LG ;
Schweizer, RAS ;
Frick, C ;
Odermatt, A .
FEBS LETTERS, 2004, 571 (1-3) :129-133
[5]   Hexose-6-phosphate dehydrogenase: linking endocrinology and metabolism in the endoplasmic reticulum [J].
Banhegyi, Gabor ;
Csala, Miklos ;
Benedetti, Angelo .
JOURNAL OF MOLECULAR ENDOCRINOLOGY, 2009, 42 (3-4) :283-289
[6]   Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysterold dehydrogenase type 1 [J].
Bujalska, IJ ;
Draper, N ;
Michailidou, Z ;
Tomlinson, JW ;
White, PC ;
Chapman, KE ;
Walker, EA ;
Stewart, PM .
JOURNAL OF MOLECULAR ENDOCRINOLOGY, 2005, 34 (03) :675-684
[7]   Circulating cortisone levels are associated with biochemical markers of bone formation and lumbar spine BMD: the Hertfordshire Cohort Study [J].
Cooper, MS ;
Syddall, HE ;
Fall, CHD ;
Wood, PJ ;
Stewart, PM ;
Cooper, C ;
Dennison, EM .
CLINICAL ENDOCRINOLOGY, 2005, 62 (06) :692-697
[8]   Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency [J].
Draper, N ;
Walker, EA ;
Bujalska, IJ ;
Tomlinson, JW ;
Chalder, SM ;
Arlt, W ;
Lavery, GG ;
Bedendo, O ;
Ray, DW ;
Laing, I ;
Malunowicz, E ;
White, PC ;
Hewison, M ;
Mason, PJ ;
Connell, JM ;
Shackleton, CHL ;
Stewart, PM .
NATURE GENETICS, 2003, 34 (04) :434-439
[9]   Hormonal regulation of oxidative and reductive activities of 11 beta-hydroxysteroid dehydrogenase in rat Leydig cells [J].
Gao, HB ;
Ge, RS ;
Lakshmi, V ;
Marandici, A ;
Hardy, MP .
ENDOCRINOLOGY, 1997, 138 (01) :156-161
[10]   11β-hydroxysteroid dehydrogenase 2 in rat Leydig cells:: Its role in blunting glucocorticoid action at physiological levels of substrate [J].
Ge, RS ;
Dong, Q ;
Niu, EM ;
Sottas, CM ;
Hardy, DO ;
Catterall, JF ;
Latif, SA ;
Morris, DJ ;
Hardy, MP .
ENDOCRINOLOGY, 2005, 146 (06) :2657-2664