Itoga H, Tamura H, Watanabe T, Suga T
Department of Clinical Biochemistry, Tokyo College of Pharmacy, Hachioji, Japan.
Biochim Biophys Acta. 1990 Jan 23;1051(1):21-8. doi: 10.1016/0167-4889(90)90169-e.
In vivo administration of nicardipine, a known calcium antagonist, suppressed the clofibrate-evoked induction of activities of peroxisomal enzymes, such as catalase, the peroxisomal fatty acyl-CoA oxidizing system, carnitine acetyltransferase and mitochondrial carnitine palmitoyltransferase in rat liver. On a time-course study, the suppression of induction in the activities of the peroxisomal fatty acyl-CoA oxidizing system and carnitine acetyltransferase was found at 5 days after the treatment, whereas the induction by clofibrate was already observed at 1 day after the treatment, suggesting that in the process of peroxisome induction by clofibrate there might be two steps, i.e., a triggering step and an enhancing step, and nicardipine might act as suppressor for the later step. The precursor-incorporation studies with [3H]leucine showed that the rate of the synthesis of the peroxisomal bifunctional enzyme was increased by 4.2-fold after clofibrate-treatment, whereas nicardipine suppressed this enhancement to only 2.2-fold of the control. The rate of degradation of this enzyme was not affected by any treatment. These results show that nicardipine affects the regulation mechanism of the biosynthesis of this enzyme. Nicardipine showed hardly any suppressive-effect on the hepatic peroxisomal enzyme induction observed in high-fat diet fed rat. Furthermore, the suppression of clofibrate-evoked induction of peroxisomal enzymes was observed also in mice. These interesting findings suggest that there is a difference in the mechanism of peroxisome proliferation and/or the induction of peroxisomal enzymes between clofibrate and physiological conditions, such as high-fat diet feeding. The suppression of drug-induced peroxisome proliferation by calcium antagonists may help in dissecting the causal relationship between the multiple effects mediated by peroxisomal proliferators.
已知的钙拮抗剂尼卡地平在体内给药可抑制氯贝丁酯诱发的大鼠肝脏过氧化物酶体酶活性的诱导，这些酶包括过氧化氢酶、过氧化物酶体脂肪酰辅酶A氧化系统、肉碱乙酰转移酶和线粒体肉碱棕榈酰转移酶。在一项时间进程研究中，发现过氧化物酶体脂肪酰辅酶A氧化系统和肉碱乙酰转移酶活性的诱导在治疗后5天受到抑制，而氯贝丁酯诱发的诱导在治疗后1天就已观察到，这表明在氯贝丁酯诱导过氧化物酶体的过程中可能有两个步骤，即触发步骤和增强步骤，尼卡地平可能对后期步骤起抑制作用。用[3H]亮氨酸进行的前体掺入研究表明，氯贝丁酯治疗后过氧化物酶体双功能酶的合成速率增加了4.2倍，而尼卡地平将这种增强抑制到仅为对照的2.2倍。该酶的降解速率不受任何处理的影响。这些结果表明尼卡地平影响该酶生物合成的调节机制。尼卡地平对高脂饮食喂养大鼠肝脏过氧化物酶体酶诱导几乎没有抑制作用。此外，在小鼠中也观察到氯贝丁酯诱发的过氧化物酶体酶诱导受到抑制。这些有趣的发现表明，氯贝丁酯与高脂饮食等生理条件之间在过氧化物酶体增殖和/或过氧化物酶体酶诱导机制上存在差异。钙拮抗剂对药物诱导的过氧化物酶体增殖的抑制可能有助于剖析过氧化物酶体增殖剂介导的多种效应之间的因果关系。
