Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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) Ca(2+)-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 Ca(2+)-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 Ca(2+)-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-driven 45Ca2+ 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 Ca(2+)-ATPase revealed a marginal increase in Ca(2+)-ATPase protein content in microsomes prepared from ciprofibrate-exposed rats compared to controls 24 hr post-exposure. These data indicate that the reduction of Ca(2+)-ATPase activity is not attributable to diminished Ca(2+)-ATPase protein content in vivo and, therefore, is due to a functional inhibition of the enzyme. Ciprofibrate also produced a concentration-dependent inhibition of rat liver ER Ca(2+)-ATPase activity in vitro (IC50 approximately 170 microM). 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+]i via inhibition of the ER Ca(2+)-ATPase. These events may lead to an environment of elevated [Ca2+]i during the early stages of ciprofibrate exposure and may serve to augment Ca(2+)-dependent processes, thus playing a pivotal role in the acute mitogenic response.
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PMID:Reduction of rat liver endoplasmic reticulum Ca(2+)-ATPase activity and mobilization of hepatic intracellular calcium by ciprofibrate, a peroxisome proliferator. 153 54

The ability of six peroxisome proliferators to modulate Ca2+ homeostasis was studied in freshly isolated rat hepatocytes. Clofibrate and bifonazole (0.5 mM) caused a transient increase in cytosolic-free Ca2+ concentration ([Ca2+]i) by releasing the intracellular inositol 1,4,5-trisphosphate-sensitive Ca2+ pool. However, the mobilization of this pool by clofibrate was only transient; a subsequent exposure of the cells to the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin resulted in a second release of the same Ca2+ store, indicating that this pool could refill from the cytosol, independently of extracellular Ca2+. By contrast, bifonazole-exposed hepatocytes no longer responded to a stimulation by thapsigargin. Bifonazole also strongly inhibited Ca2+ influx. Ciprofibrate and nafenopin (0.5 mM) produced increases in [Ca2+]i that were sustained, even in the absence of extracellular Ca2+. The [Ca2+]i response was not due to release of the inositol 1,4,5-trisphosphate-sensitive Ca2+ pool and was not inhibited by prior treatment with the protonophore carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone, but was slightly antagonized by prior exposure to the Ca2+ ionophore ionomycin. Pretreating the cells with nafenopin completely abolished the response elicited by ciprofibrate, and vice versa. By contrast to the other peroxisome proliferators, WY-14,643 and bezafibrate (1 mM) increased cytosolic free Ca2+ only by approximately 30 nM. In conclusion, the structurally diverse peroxisome proliferators tested in this study all produced changes in [Ca2+]i in hepatocytes but through the redistribution of different internal Ca2+ pools. Further studies are needed to determine whether any of the observed Ca2+ changes have a role in the pleiotropic effects elicited by peroxisome proliferators.
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PMID:Diverse mechanisms of calcium mobilization by peroxisome proliferators in rat hepatocytes. 787 41

Ciprofibrate (CP), a peroxisome proliferator, has been shown to reduce rat liver endoplasmic reticulum (ER) Ca(2+)-ATPase activity both in vitro and in vivo. The ER Ca(2+)-ATPase is highly susceptible to thiol reactivity, and maintenance of maximal enzyme activity is critically dependent upon the integrity of these thiol groups. We therefore investigated whether CP alters ER Ca(2+)-ATPase thiol groups as a possible mechanism of enzyme inhibition. Using a thiol immunoblot technique, free thiol groups specifically on the ER Ca(2+)-ATPase were localized. Exposure of freshly isolated rat liver microsomes to CP (500 microM) resulted in a loss of sulfhydryl reactivity on the ER Ca(2+)-ATPase protein at 107 kDa, as identified using the thiol immunoblot assay. However, when rat liver microsomes were exposed to CP in the presence of reduced glutathione (GSH), thiol groups on the ER Ca(2+)-ATPase were protected. Also, the reduction of ER Ca(2+)-ATPase activity by CP could be ameliorated by co-incubation of rat liver microsomes with GSH. These observations indicate that CP reduces rat liver ER Ca(2+)-ATPase activity through interactions with free thiol groups located on this enzyme.
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PMID:Alteration of rat liver endoplasmic reticulum Ca(2+)-ATPase thiol integrity by ciprofibrate, a peroxisome proliferator. 851 90