Interactions between dehydroepiandrosterone and glucocorticoid metabolism in pig kidney: nuclear and microsomal 11beta-hydroxysteroid dehydrogenases.
Interactions between dehydroepiandrosterone and glucocorticoid metabolism in pig kidney: nuclear and microsomal 11beta-hydroxysteroid dehydrogenases.
复制标题
猪肾中脱氢表雄酮和糖皮质激素代谢之间的相互作用：核和微粒体 11β-羟基类固醇脱氢酶。
DOI：
10.1016/j.abb.2005.07.010
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发表时间：
2005
影响因子：
3.9
通讯作者：
Prough,RussellA
中科院分区：
文献类型：
--
作者：
Robinzon,Boaz;Prough,RussellA
11β-羟基类固醇脱氢酶1型（11β HSD 1）通过可逆地将11-酮-GC转化为11-羟基-GC来激活糖皮质激素（GC），而11β HSD 2和11β HSD 3仅催化逆反应。最近，大鼠和人的11βHSDs显示7α-和7β-羟基脱氢表雄酮（7α-或7β-OH-DHEA）与7-oxo-DHEA相互转化。我们报道了猪肾微粒体（PKMc）和细胞核（PKN）在NAD+下比在NADP+下以更高的速率将7α-OH-DHEA氧化为7-oxo-DHEA。皮质酮（CS）、脱氢皮质酮（DHC）、11α-和11β-羟孕酮和甘珀酸完全抑制这些反应，而7-oxo-DHEA仅抑制NAD+依赖的反应。相反，CS氧化不被7α-OH-DHEA或7-oxo-DHEA抑制。PKMc和PKN不能用NADPH或NADH将7-oxo-DHEA转化为7-OH-DHEA。最后，PKN含有高亲和力的NADPH依赖性11βHSD，可将DHC还原为CS。GC对DHEA代谢物相互转化的影响可能具有临床意义，因为DHEA及其7-氧化衍生物已被提出用于治疗人类自身免疫性和炎症性疾病。
The 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) activates glucocorticoids (GC) by reversibly converting 11-keto-GC to 11-hydroxy-GC, while 11βHSD2 and 11βHSD3 only catalyzes the reverse reaction. Recently, rat and human 11βHSDs were shown to interconvert 7α- and 7β-hydroxy-dehydroepiandrosterone (7α- or 7β-OH-DHEA) with 7-oxo-DHEA. We report that pig kidney microsomes (PKMc) and nuclei (PKN) oxidize 7α-OH-DHEA to 7-oxo-DHEA at higher rates with NAD+, than with NADP+. Corticosterone (CS), dehydrocoticosterone (DHC), 11α- and 11β-hydroxyprogesterone, and carbenoxolone completely inhibited these reactions, while 7-oxo-DHEA only inhibited the NAD+-dependent reaction. Conversely, CS oxidation was not inhibited by 7α-OH-DHEA or 7-oxo-DHEA. PKMc and PKN did not convert 7-oxo-DHEA to 7-OH-DHEA with either NADPH or NADH. Finally, PKN contained a high affinity, NADPH-dependent 11βHSD that reduces DHC to CS. The GC effects on interconversion of DHEA metabolites may have clinical significance, since DHEA and its 7-oxidized derivatives have been proposed for treatment of human autoimmune and inflammatory disorders.