多柔比星致 C57Bl/6 小鼠心脏细胞色素 P450 基因表达的性别依赖性改变。
Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl/6 mice.
机构信息
Department of Experimental and Clinical Pharmacology, University of Minnesota, 308 Harvard St S.E, Minneapolis, MN 55455 USA.
Veterinary Clinical Sciences Department, University of Minnesota, 1352 Boyd Ave, St. Paul, MN 55108 USA.
出版信息
Biol Sex Differ. 2017 Jan 7;8:1. doi: 10.1186/s13293-016-0124-4. eCollection 2017.
BACKGROUND
There is inconclusive evidence about the role of sex as a risk factor for doxorubicin (DOX)-induced cardiotoxicity. Recent experimental studies have shown that adult female rats are protected against DOX-induced cardiotoxicity. However, the mechanisms of this sexual dimorphism are not fully elucidated. We have previously demonstrated that DOX alters the expression of several cytochrome P450 (CYP) enzymes in the hearts of male rats. Nevertheless, the sex-dependent effect of DOX on the expression of CYP enzymes is still not known. Therefore, in the present study, we determined the effect of acute DOX exposure on the expression of CYP genes in the hearts of both male and female C57Bl/6 mice.
METHODS
Acute DOX cardiotoxicity was induced by a single intraperitoneal injection of 20 mg/kg DOX in male and female adult C57Bl/6 mice. Cardiac function was assessed 5 days after DOX exposure by trans-thoracic echocardiography. Mice were euthanized 1 day or 6 days after DOX or saline injection. Thereafter, the hearts were harvested and weighed. Heart sections were evaluated for pathological lesions. Total RNA was extracted and expression of natriuretic peptides, inflammatory and apoptotic markers, and CYP genes was measured by real-time PCR.
RESULTS
Adult female C57Bl/6 mice were protected from acute DOX-induced cardiotoxicity as they show milder pathological lesions, less inflammation, and faster recovery from DOX-induced apoptosis and DOX-mediated inhibition of beta-type natriuretic peptide. Acute DOX exposure altered the gene expression of multiple CYP genes in a sex-dependent manner. In 24 h, DOX exposure caused male-specific induction of Cyp1b1 and female-specific induction of Cyp2c29 and Cyp2e1.
CONCLUSIONS
Acute DOX exposure causes sex-dependent alteration of cardiac CYP gene expression. Since cardiac CYP enzymes metabolize several endogenous compounds to biologically active metabolites, sex-dependent alteration of CYP genes may play a role in the sexual dimorphism of acute DOX-induced cardiotoxicity.
背景
性别的作用是否为多柔比星（DOX）诱导的心脏毒性的风险因素，目前仍存在不确定的证据。最近的实验研究表明，成年雌性大鼠对 DOX 诱导的心脏毒性具有保护作用。然而，这种性别二态性的机制尚未完全阐明。我们之前已经证明，DOX 会改变雄性大鼠心脏中几种细胞色素 P450（CYP）酶的表达。尽管如此，DOX 对 CYP 酶表达的性别依赖性影响仍不清楚。因此，在本研究中，我们确定了急性 DOX 暴露对雄性和雌性 C57Bl/6 小鼠心脏中 CYP 基因表达的影响。
方法
通过单次腹腔注射 20mg/kg DOX 在雄性和雌性成年 C57Bl/6 小鼠中诱导急性 DOX 心脏毒性。DOX 暴露 5 天后通过经胸超声心动图评估心功能。在 DOX 或生理盐水注射后 1 天或 6 天处死小鼠。然后，取出心脏并称重。评估心脏切片的病理病变。提取总 RNA，通过实时 PCR 测量利钠肽、炎症和凋亡标志物以及 CYP 基因的表达。
结果
成年雌性 C57Bl/6 小鼠对急性 DOX 诱导的心脏毒性具有保护作用，因为它们表现出较轻的病理病变、较少的炎症以及更快地从 DOX 诱导的凋亡和 DOX 介导的β型利钠肽抑制中恢复。急性 DOX 暴露以性别依赖的方式改变了多个 CYP 基因的表达。在 24 小时内，DOX 暴露引起雄性特异性 Cyp1b1 诱导和雌性特异性 Cyp2c29 和 Cyp2e1 诱导。
结论
急性 DOX 暴露引起心脏 CYP 基因表达的性别依赖性改变。由于心脏 CYP 酶将几种内源性化合物代谢为生物活性代谢物，因此 CYP 基因的性别依赖性改变可能在急性 DOX 诱导的心脏毒性的性别二态性中起作用。
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