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.