Reduction of rat liver endoplasmic reticulum Ca(2+)-ATPase activity and mobilization of hepatic intracellular calcium by ciprofibrate, a peroxisome proliferator.
Reduction of rat liver endoplasmic reticulum Ca(2+)-ATPase activity and mobilization of hepatic intracellular calcium by ciprofibrate, a peroxisome proliferator.
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DOI：
10.1016/0006-2952(92)90583-5
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发表时间：
1992-02
影响因子：
5.8
通讯作者：
A. Bennett;G. Williams
中科院分区：
文献类型：
--
作者：
A. Bennett;G. Williams
Ciprofibrate, a peroxisome proliferating agent, induces cell proliferation in rodent liver during the early periods of exposure. Since Ca2+plays an important role in mitogenesis, we have investigated the effects of ciprofibrate on hepatic endoplasmic reticulum (ER) Ca2+-ATPase, which in part regulates Ca2+homeostasis. A single oral dose of 200 mg/kg ciprofibrate to male F344 rats produced a transient decrease in liver microsomal Ca2+-ATPase activity to 48% of control levels at 24 hr post-exposure. Activity had returned to control levels by 48 and 72 hr after exposure. The decrease in Ca2+-ATPase activity was not a function of non-specific enzymatic inhibition, since activity of another microsomal enzyme, glucose-6-phosphatase, was not altered in ciprofibrate-exposed rats. Using an ATP-driven45Ca2+accumulation assay, rats exposed to 25, 100 and 200 mg/kg ciprofibrate exhibited a dose-dependent inhibition of liver microsomal Ca2+accumulation at 24 hr post-exposure. Analysis of Western immunoblots using a polyclonal antibody to the liver ER Ca2+-ATPase revealed a marginal increase in Ca2+-ATPase protein content in microsomes prepared from ciprofibrate-exposed rats compared to controls 24 hr post-exposure. These data indicate that the reduction of Ca2+-ATPase activity is not attributable to diminished Ca2+-ATPase protein contentin vivoand, therefore, is due to a functional inhibition of the enzyme. Ciprofibrate also produced a concentration-dependent inhibition of rat liver ER Ca2+-ATPase activityin vitro(IC50≈ 170 μM). In freshly isolated rat hepatocytes, ciprofibrate elevated the free intracellular calcium concentration ([Ca2+]i) in the presence and absence of extracellular calcium. Collectively, these results suggest that Ciprofibrate mobilizes hepatic [Ca2+]ivia inhibition of the ER Ca2+-ATPase. These events may lead to an environment of elevated [Ca2+]iduring the early stages of ciprofibrate exposure and may serve to augment Ca2+-dependent processes, thus playing a pivotal role in the acute mitogenic response.
