Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN 55455, USA.
Int J Mol Sci. 2020 Feb 14;21(4):1279. doi: 10.3390/ijms21041279.
Doxorubicin (DOX) is an effective chemotherapeutic agent used to treat a wide variety of malignancies. In addition to its multi-organ toxicity, DOX treatment has been shown to induce systemic inflammation in patients and experimental animals. Inflammation alters the expression of hepatic cytochrome P450 (CYP) enzymes, which play important roles in drug metabolism and DOX-induced toxicity. Significant sex differences have been reported in DOX-induced toxicity; however, sex differences in DOX-induced systemic inflammation and the potential effects on hepatic CYP expression have not been determined. In the current work, male and female C57Bl/6 mice were administered DOX (20 mg/kg by intraperitoneal injection), and groups of mice were sacrificed 24 and 72 h after DOX administration. DOX elicited a systemic inflammatory response in both male and female mice, but the inflammatory response was stronger in male mice. DOX altered the expression of hepatic CYP isoforms in a sex-dependent manner. Most notably, inhibition of Cyp2c29 and Cyp2e1 was stronger in male than in female mice, which paralleled the sex differences in systemic inflammation. Therefore, sex differences in DOX-induced systemic inflammation may lead to sexually dimorphic drug interactions, in addition to contributing to the previously reported sexual dimorphism in specific DOX-induced organ toxicity.
多柔比星（DOX）是一种有效的化疗药物，用于治疗多种恶性肿瘤。除了多器官毒性外，DOX 治疗已被证明会在患者和实验动物中引起全身炎症。炎症改变了肝细胞色素 P450（CYP）酶的表达，这些酶在药物代谢和 DOX 诱导的毒性中起着重要作用。已经报道了 DOX 诱导的毒性存在显著的性别差异；然而，DOX 诱导的全身炎症的性别差异及其对肝 CYP 表达的潜在影响尚未确定。在目前的工作中，雄性和雌性 C57Bl/6 小鼠给予 DOX（通过腹腔注射 20mg/kg），并在 DOX 给药后 24 和 72 小时处死各组小鼠。DOX 在雄性和雌性小鼠中均引起全身炎症反应，但雄性小鼠的炎症反应更强。DOX 以性别依赖的方式改变肝 CYP 同工酶的表达。值得注意的是，Cyp2c29 和 Cyp2e1 的抑制作用在雄性小鼠中比在雌性小鼠中更强，这与全身炎症的性别差异一致。因此，DOX 诱导的全身炎症的性别差异可能导致性别依赖性药物相互作用，除了导致先前报道的特定 DOX 诱导的器官毒性中的性别差异。
