Effect of Clofibrate Treatment and Withdrawal on Hepatic Iron Metabolism in Rat
| Autor: | Yang-Li Wang, 王雅麗 |
|---|---|
| Rok vydání: | 2002 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 90 Hypolipidemic drug clofibrate alters iron homeostasis, including decreased transferrin（Tf）mRNA and increased protein and activity of mitochondrial aconitase（m-ACO）in the liver. Since Tf mRNA is elevated and m-ACO is down-regulated by iron deficiency, clofibrate may counteract the effect of iron deficiency on hepatic iron homeostasis. Therefore, this study was aimed to explore (1) the effect of clofibrate on hepatic iron homeostasis in the presence of iron deficiency and (2) the effect of drug withdrawal after chronic clofibrate treatment in two experiments. Wistar rats were used for the two experiments. At the end of the indicated treatment, rats were fasted overnight, then sacrificed, and liver and blood were collected and processed for later analysis. RNA binding activities of IRP1 and IRP2 were measured using EMSA. Message RNA was measured using Northern blot analysis. In experiment one, twenty rats（10 each）were assigned to two dietary iron groups (35 ppm and 2-3 ppm) for 4 weeks, then each group was subdivided into two for two dose levels of clofibrate（0 and 0.5%）for 10 days.The results showed that in the presence of iron deficiency, clofibrate significantly depressed Tf mRNA, increased the mRNA levels of m-ACO, succinate dehydrogenase (SDH) and NADH dehydrogenase (NADH DH), and offset iron regulatory protein2（IRP2）activation. The depressed Tf mRNA and serum Tf levels explained the anemia associated with the clinical use of clofibrate. In experiment two, twenty-five rats fed on a low iron diet（15 ppm Fe）were divided into five groups and among which four groups were also treated with 0.5% clofibrate in the diet. Starting from the sixtieth day, clofibrate was withdrawn from one group of rats every week for three consecutive weeks. The group without clofibrate treatment served as normal control and the group without drug withdrawal served as drug control. All rats were sacrificed after 81 days of feeding. The results indicated that the elevated mRNA levels of m-ACO, SDH and NADH DH, the depressed mRNA levels of Tf, TfR and P-type ATPase 7B, and the reduced IRP2 activity caused by clofibrate treatment, all recovered to the level of the normal control for all three drug-withdrawn groups, indicating a reversible effect by clofibrate. In conclusion, clofibrate couteracted the hepatic adaptation of iron homeostasis in response to iron deficiency, and the drug effect can be reversed by drug withdrawal for as short as one week. Intermittent drug withdrawal may help eliminate the adverse hepatic and hematological effects associated with clofibrate. Key words：clofibrate, iron deficiency, mitochondrial aconitase, transferrin, IRP1 |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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