Abstract
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.
Highlights
Doxorubicin (DOX) is an effective chemotherapeutic agent used to treat a wide variety of solid and hematological malignancies
We determined the effect of acute DOX administration on serum level of key inflammatory mediators, interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), in adult male and female C57Bl/6 mice 24 h post-treatment
The serum levels of IL-6 and TNF-alpha were below the lower limit of quantification (LLQ) in control male and female mice (Figure 1)
Summary
Doxorubicin (DOX) is an effective chemotherapeutic agent used to treat a wide variety of solid and hematological malignancies. The clinical utility of DOX is limited by its multi-organ toxicity. DOX is known for its cardiotoxic effects that may lead to cardiac dysfunction and heart failure [1]. DOX has been shown to cause hepatotoxicity [2,3,4,5,6], gastro-intestinal toxicity [7], and nephrotoxicity [8,9]. In addition to organ-specific inflammatory changes, DOX treatment has been shown to cause systemic inflammation in cancer patients [10], piglets [7], and rodents [15]
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