阿霉素和C-13脱氧阿霉素对兰尼碱受体基因表达的影响。

Doxorubicin and C-13 deoxydoxorubicin effects on ryanodine receptor gene expression.

作者信息

Gambliel Herve A, Burke Briant E, Cusack Barry J, Walsh Gerald M, Zhang Yumei L, Mushlin Philip S, Olson Richard D

机构信息

Department of Research and Development, Department of Veteran's Affairs Medical Center, Boise, Idaho 83702, USA.

出版信息

Biochem Biophys Res Commun. 2002 Mar 1;291(3):433-8. doi: 10.1006/bbrc.2002.6380.

DOI:10.1006/bbrc.2002.6380

PMID:11855807

Abstract

Chronic anthracycline administration to rabbits causes impairment of cardiac contractility and decreased gene expression of the calcium-induced calcium release channel of sarcoplasmic reticulum (SR), the ryanodine receptor (RYR2). The C-13 hydroxy metabolite (doxorubicinol), formed in the heart, has been hypothesized to contribute to anthracycline cardiotoxicity. C-13 deoxydoxorubicin is an analog unable to form the C-13 hydroxy metabolite. Therefore, doxorubicin, C-13 deoxydoxorubicin, or saline was administered to rabbits (1 mg/kg iv twice weekly for 8 weeks). Left ventricular fractional shortening (LVFS) was decreased by chronic treatment with doxorubicin (28 +/- 2%; P < 0.05), but not C-13 deoxydoxorubicin (33 +/- 2%) compared to age-matched pair-fed controls. Doxorubicin, but not C-13 deoxydoxorubicin, caused a significant reduction (P < 0.02) in the ratio of RYR2/Ca-Mg ATPase (SERCA2) mRNA levels (0.57 +/- 0.1 vs 1.22 +/- 0.2, respectively) in the left ventricle. This suggests that doxorubicinol may contribute to the downregulation of cardiac RYR2 expression in chronic doxorubicin cardiotoxicity.

摘要

长期给兔子施用蒽环类药物会导致心脏收缩功能受损，以及肌浆网（SR）的钙诱导钙释放通道即兰尼碱受体（RYR2）的基因表达降低。据推测，在心脏中形成的C-13羟基代谢物（阿霉素醇）会导致蒽环类药物的心脏毒性。C-13脱氧阿霉素是一种无法形成C-13羟基代谢物的类似物。因此，给兔子施用阿霉素、C-13脱氧阿霉素或生理盐水（每周静脉注射1 mg/kg，共8周，每周两次）。与年龄匹配的成对喂养对照组相比，长期使用阿霉素治疗会降低左心室缩短分数（LVFS）（28±2%；P<0.05），而C-13脱氧阿霉素则不会（33±2%）。阿霉素而非C-13脱氧阿霉素会导致左心室中RYR2/Ca-Mg ATP酶（SERCA2）mRNA水平的比率显著降低（P<0.02）（分别为0.57±0.1和1.22±0.2）。这表明阿霉素醇可能在慢性阿霉素心脏毒性中导致心脏RYR2表达下调。