Dehydroepiandrosterone 3 beta-sulphate is an endogenous activator of the peroxisome-proliferation pathway: induction of cytochrome P-450 4A and acyl-CoA oxidase mRNAs in primary rat hepatocyte culture and inhibitory effects of Ca(2+)-channel blockers.
Dehydroepiandrosterone 3 beta-sulphate is an endogenous activator of the peroxisome-proliferation pathway: induction of cytochrome P-450 4A and acyl-CoA oxidase mRNAs in primary rat hepatocyte culture and inhibitory effects of Ca(2+)-channel blockers.
复制标题
DeHydroepiandrosterone 3 beta-sulfate 是过氧化物酶体增殖途径的内源性激活剂：在原代大鼠肝细胞培养物中诱导细胞色素 P-450 4A 和酰基辅酶 A 氧化酶 mRNA 以及 Ca(2 ) 通道阻滞剂的抑制作用。
DOI：
10.1042/bj3010753
复制
发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Waxman,DJ
中科院分区：
文献类型：
--
作者：
Ram,PA;Waxman,DJ
使用原代大鼠肝细胞培养系统评估了与肾上腺雄激素脱氢表雄酮（5-雄烯-3 β-醇-17-酮; DHEA）相关的类固醇在调节脂肪酸代谢中活性过氧化物酶体和细胞色素P-450 4A（CYP 4A）酶表达中的作用。通过使用基因特异性寡核苷酸探针的Northern印迹分析判断，将肝细胞暴露于过氧化物酶体增殖剂氯贝酸（10-250 μ M）48-96 h导致CYP 4A蛋白、CYP 4A 1、CYP 4A 2和CYP 4A 3 mRNA以及编码两种形式的过氧化物酶体酰基辅酶A氧化酶（ACOX-I和ACOX-II）的mRNA显著增加。虽然DHEA治疗在体内是有效的诱导这些mRNA在大鼠肝脏中，它没有影响在培养的肝细胞。相比之下，用DHEA 3 β-硫酸盐（DHEA-S; 10-250 μ M）处理细胞刺激CYP 4A和ACOX mRNA水平的主要增加。对几种类似物的检查表明，3 β-硫酸盐优于17 β-硫酸盐类固醇，3 α-羟基-17 β-硫酸盐衍生物无活性（DHEA-S > 5-雄甾烯-3 β，17 β-二醇3-硫酸酯约5 α-雄甾烯-3 β-醇-17-酮3-硫酸酯> 5-雄甾烯-3 β，17 β，17 β-二醇17-硫酸酯约5 β-雄甾烷-3 α-醇-17-酮3-硫酸酯>> 5 α-雄甾烷-3 α，17 β-二醇17-硫酸酯）。DHEA-S或氯贝酸对CYP 4A mRNA的诱导作用被结构不同的Ca（2+）通道拮抗剂（尼卡地平、硝苯地平和地尔硫卓; 50 μ M）部分阻断，表明类固醇和贝特类CYP 4A诱导剂均通过Ca（2+）依赖性途径刺激过氧化物酶增殖反应。单独维甲酸轻微诱导CYP 4A mRNA，但不增强氯贝特或DHEA-S的诱导作用。由于DHEA-S对应于生理上重要的主要循环雄激素，这些发现表明它可能作为肝过氧化物酶体酶水平的内源性调节剂。他们进一步表明，Ca（2+）通道阻滞剂可能是进一步研究内源性类固醇和贝特类药物诱导过氧化物酶体增殖的潜在细胞机制以及这些事件与过氧化物酶体增殖物激活受体激活的关系的有用药理学工具。
The role of steroids related to the adrenal androgen dehydroepiandrosterone (5-androstene-3 beta-ol-17-one; DHEA) in regulating the expression of peroxisomal and cytochrome P-450 4A (CYP4A) enzymes active in fatty acid metabolism was assessed using a primary rat hepatocyte culture system. Exposure of hepatocytes to the peroxisome proliferator, clofibric acid (10-250 microM), for 48-96 h led to substantial increases in CYP4A protein, CYP4A1, CYP4A2 and CYP4A3 mRNAs, and the mRNAs encoding both forms of peroxisomal acyl-CoA oxidase (ACOX-I and ACOX-II), as judged by Northern-blot analysis using gene-specific oligonucleotide probes. Although DHEA treatment in vivo is effective in inducing these mRNAs in rat liver, it had no effect in the cultured hepatocytes. In contrast, treatment of the cells with DHEA 3 beta-sulphate (DHEA-S; 10-250 microM) stimulated major increases in CYP4A and ACOX mRNA levels. Examination of several analogues indicated a preference for 3 beta-sulphate over 17 beta-sulphated steroids and the inactivity of a 3 alpha-hydroxy-17 beta-sulphate derivative (DHEA-S > 5-androstene-3 beta,17 beta-diol 3-sulphate approximately 5 alpha-androstene-3 beta-ol-17-one 3-sulphate > 5-androstene-3 beta, 17 beta,17 beta-diol 17-sulphate approximately 5 beta-androstane-3 alpha-ol-17-one 3-sulphate >> 5 alpha-androstane-3 alpha, 17 beta-diol 17-sulphate). Induction of CYP4A mRNAs by either DHEA-S or clofibric acid was partially blocked by structurally diverse Ca(2+)-channel antagonists (nicardipine, nifedipine and diltiazem; 50 microM), suggesting that both the steroidal and fibrate classes of CYP4A inducers stimulate peroxisomal-proliferative responses via a Ca(2+)-dependent pathway. Retinoic acid alone slightly induced CYP4A mRNAs but did not enhance the induction by clofibrate or DHEA-S. As DHEA-S corresponds to a physiologically important major circulating androgen, these findings suggest that it may serve as an endogenous regulator of hepatic peroxisome enzyme levels. They further suggest that Ca(2+)-channel blockers may be useful pharmacological tools for the further study of the underlying cellular mechanism whereby endogenous steroids and fibrate drugs induce peroxisome proliferation, and the relationship of these events to activation of the peroxisome proliferator-activated receptor.