Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice.
Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice.
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谷胱甘肽S-转移酶P可预防小鼠环磷酰胺诱导的心脏毒性。
DOI：
10.1016/j.taap.2015.03.029
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发表时间：
2015-06-01
影响因子：
3.8
通讯作者：
Bhatnagar, Aruni
中科院分区：
文献类型：
--
作者：
Conklin, Daniel J.;Haberzettl, Petra;Jagatheesan, Ganapathy;Baba, Shahid;Merchant, Michael L.;Prough, Russell A.;Williams, Jessica D.;Prabhu, Sumanth D.;Bhatnagar, Aruni
使用环磷酰胺(CY)的大剂量化疗方案经常与心脏毒性有关，可能导致心肌细胞损伤和充血性心力衰竭。然而，CY心脏毒性作用的调节机制仍不清楚。由于CY被转化为一种有毒的反应性CY代谢物丙烯醛，可引起广泛的蛋白质修饰和心肌损伤，因此我们研究了丙烯醛代谢酶谷胱甘肽S转移酶P(GSTP)在野生型(WT)和GSTP缺失小鼠CY心脏毒性中的作用。环磷酰胺(100-300 mg/kg)治疗使GSTP阴性小鼠的血浆肌酸激酶-MB亚型(CK·MB)水平和心/体重比显著增加(P<0.05)。除了急性CY治疗后轻微但显著的超声心动图变化外，GSTP不足还与c-jun和p38的更大磷酸化以及白蛋白和蛋白-丙烯醛加合物在心脏中的更大积聚有关。质谱分析显示，CY处理的小鼠心脏中的白蛋白、激肽释放酶-1相关多肽酶、肌红蛋白和转明胶-2可能被丙烯醛显著修饰。丙烯醛(小剂量，1-5 mg/kg)治疗还导致心/体重比增加和心肌收缩功能改变。丙烯醛在GSTP缺失和WT小鼠中引起类似的低血压。GSTP缺失的小鼠也比WT小鼠更容易受到高剂量丙烯醛(10-20 mg/kg)相关的死亡的影响。总之，这些结果表明CY的心脏毒性在一定程度上受GSTP的调节，GSTP通过排毒丙烯醛来防止CY毒性。因此，心脏GSTP水平低的人或具有低丙烯醛代谢能力的GSTP多态形式的人可能对CY毒性更敏感。环磷酰胺(CY)处理导致P450介导的磷酰胺芥末和丙烯醛(3-丙二醛)的代谢形成。丙烯醛可被谷胱甘肽S转移酶P-通过与谷胱甘肽结合而代谢和解毒，或与循环和心脏蛋白反应形成蛋白-丙烯醛加合物，可能导致心脏损伤、血管通透性增加、水肿和急性心脏毒性。在低剂量暴露下，这一事件是可逆的，但在高水平的环磷酰胺治疗和/或易感个体中(如hGSTP1基因多态性)，环磷酰胺引起的心脏毒性增加，并可能发生猝死。
High-dose chemotherapy regimens using cyclophosphamide (CY) are frequently associated with cardiotoxicity that could lead to myocyte damage and congestive heart failure. However, the mechanisms regulating the cardiotoxic effects of CY remain unclear. Because CY is converted to an unsaturated aldehyde acrolein, a toxic, reactive CY metabolite that induces extensive protein modification and myocardial injury, we examined the role of glutathione S-transferase P (GSTP), an acrolein-metabolizing enzyme, in CY cardiotoxicity in wild-type (WT) and GSTP-null mice. Treatment with CY (100-300 mg/kg) increased plasma levels of creatine kinase-MB isoform (CK·MB) and heart-to-body weight ratio to a significantly greater extent in GSTP-null than WT mice. In addition to modest yet significant echocardiographic changes following acute CY-treatment, GSTP insufficiency was associated with greater phosphorylation of c-Jun and p38 as well as greater accumulation of albumin and protein-acrolein adducts in the heart. Mass spectrometric analysis revealed likely prominent modification of albumin, kallikrein-1-related peptidase, myoglobin and transgelin-2 by acrolein in the hearts of CY-treated mice. Treatment with acrolein (low dose, 1-5 mg/kg) also led to increased heart-to-body weight ratio and myocardial contractility changes. Acrolein induced similar hypotension in GSTP-null and WT mice. GSTP-null mice also were more susceptible than WT mice to mortality associated with high-dose acrolein (10-20 mg/kg). Collectively, these results suggest that CY cardiotoxicity is regulated, in part, by GSTP, which prevents CY toxicity by detoxifying acrolein. Thus, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to CY toxicity. Cyclophosphamide (CY) treatment results in P450-mediated metabolic formation of phosphoramide mustard and acrolein (3-propenal). Acrolein is either metabolized and detoxified by glutathione S-transferase P- (GSTP) via conjugation with GSH or acrolein can react with circulating and cardiac proteins to form protein-acrolein adducts that may contribute to cardiac injury, increased vascular permeability and edema and acute cardiotoxicity. Under low dose exposure, this event is reversible but at high levels of CY treatment and/or in susceptible individuals (e.g., hGSTP1 polymorphism), CY-induced cardiotoxicity is augmented and sudden death may occur.
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影响因子：
4.8
作者：
Elsby, R;Kitteringham, NR;Park, BK
通讯作者：
Park, BK
影响因子：
5.8
作者：
COX, PJ
通讯作者：
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影响因子：
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作者：
Al-Rawithi, S;El-Yazigi, A;Nicholls, PJ
通讯作者：
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影响因子：
2.9
作者：
Alderton, AL;Faustman, C;Hill, DW
通讯作者：
Hill, DW
DOI：
10.1152/ajpheart.00120.2011
发表时间：
2011-11-01
影响因子：
4.8
作者：
Ismahil, Mohamed Ameen;Hamid, Tariq;Prabhu, Sumanth D.
通讯作者：
Prabhu, Sumanth D.