Role of testosterone in the induction of hepatic peroxisome proliferation by clofibrate.
Role of testosterone in the induction of hepatic peroxisome proliferation by clofibrate.
复制标题
睾酮在安妥明诱导肝过氧化物酶体增殖中的作用。
DOI：
10.1016/0026-0495(94)90240-2
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Winters,SJ
中科院分区：
文献类型：
--
作者：
Paul,HS;Sekas,G;Winters,SJ
肝过氧化物酶体增殖是由许多药物诱导的，包括氯贝特。过氧化物酶体的持续增殖与肝细胞癌的发生有关。在本研究中，我们研究了睾酮在氯贝丁酯诱导的过氧化物酶体增殖中的作用。研究了三组雄性大鼠（完整、去势和去势睾丸酮替代）。过氧化物酶体的增殖是通过喂食氯贝特（0.25%，0.50%和1.0%的饮食）2周来诱导的。通过测量总过氧化物酶体β-氧化活性来监测过氧化物酶体增殖。在完整大鼠中，过氧化物酶体β-氧化活性（nmol/min/mg蛋白）以剂量依赖性方式增加，在0%、0.25%、0.50%和1.0%的氯贝特剂量下分别为7.2 ± 0.4、52.6 ± 7.5、63.2 ± 3.7和92.4 ± 4.0。相反，在去势大鼠中，在0.25%和0.50%的氯贝丁酯水平下，总过氧化物酶体β-氧化活性显著降低（P<0.01）（分别为25.8 ± 2.7和42.5 ± 2.2），但在1.0%的氯贝丁酯水平下则不显著（P> 0.05）（85.0 ± 6.3）。替吉奥替代去势大鼠可恢复过氧化物酶体β-氧化活性。为了确定上述结果是否与存在或不存在睾酮时氯贝特的代谢有关，我们测定了血清氯贝特水平。这些水平在去势大鼠中比完整大鼠或睾酮处理的去势大鼠低50%。肝尿苷二磷酸（UDP）-葡萄糖醛酸转移酶的活性，催化氯贝丁酯的葡萄糖醛酸化的酶，使用胆红素或4-甲基伞形酮作为底物进行测量，发现不受去势或睾酮治疗。我们的结论是：（1）氯贝丁酯诱导的过氧化物酶体增殖在睾酮缺乏的情况下是钝化的;（2）在肝过氧化物酶体对氯贝丁酯的反应中的性二态性是由于在睾酮存在的情况下氯贝丁酯的循环浓度较高;（3）睾酮和氯贝丁酯之间的代谢相互作用对这种作用仍有待研究。
Hepatic peroxisome proliferation is induced by a number of agents, including clofibrate. Sustained proliferation of peroxisomes is associated with the development of hepatocellular carcinoma. In the present study, we have investigated the role of testosterone in peroxisome proliferation induced by clofibrate. Three groups of male rats (intact, castrated, and castrated replaced with testosterone) were studied. Proliferation of peroxisomes was induced by feeding clofibrate (0.25%, 0.50%, and 1.0% of diet) for 2 weeks. Peroxisome proliferation was monitored by measuring total peroxisomal β-oxidation activity. In intact rats, the peroxisomal β-oxidation activity (nmol/min/mg protein) increased in a dose-dependent manner and was 7.2 ± 0.4, 52.6 ± 7.5, 63.2 ± 3.7, and 92.4 ± 4.0 at clofibrate doses of 0%, 0.25%, 0.50%, and 1.0%, respectively. In contrast, in castrated rats, the total peroxisomal β-oxidation activity was significantly (P< .01) lower at clofibrate levels of 0.25% and 0.50% (25.8 ± 2.7 and 42.5 ± 2.2, respectively), but not at the clofibrate level of 1.0% (85.0 ± 6.3). Testosterone replacement of castrated rats restored the peroxisomal β-oxidation activity. To determine whether the above results were related to the metabolism of clofibrate in the absence or presence of testosterone, we measured serum clofibrate levels. These levels were 50% lower in castrated rats than in intact rats or in testosterone-treated castrated rats. The activity of hepatic uridine diphosphate (UDP)-glucuronyltransferase, the enzyme catalyzing the glucuronidation of clofibrate, was measured using either bilirubin or 4-methylumbelliferone as substrates and was found to be unaffected by castration or testosterone treatment. We conclude that (1) clofibrate-induced proliferation of peroxisomes is blunted in the absence of testosterone; (2) the sexual dimorphism in the response of hepatic peroxisomes to clofibrate results from higher circulating clofibrate concentration in the presence of testosterone; and (3) the metabolic interaction between testosterone and clofibrate for this effect remains to be investigated.