Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

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.

Doxorubicin Paradoxically Ameliorates Tumor-Induced Inflammation in Young Mice

“…Finally, we wanted to investigate the effects of DOX and the tumor on systemic inflammation. DOX itself has been shown in previous models to induce systemic inflammation [11,61]. However, the DOX regimen used in our study did not cause a significant increase in serum inflammatory markers in tumor-free mice.…”

“…We have previously reported that acute DOX administration elicited a systemic inflammatory response in adult C57BL/6N mice [11]. Herein, we determined the effect of chronic DOX administration on serum levels of the inflammatory markers IL-6 and TNF-α, in juvenile tumor-free and tumor-bearing mice.…”

“…DOX has been shown to trigger systemic inflammation [10][11][12] and an inflammatory response in multiple organs including the heart [13], kidney [14], and liver [15]. This inflammatory response has been shown to promote DOX-induced adverse effects [16,17].…”

CYP1B1 as a therapeutic target in cardio-oncology

“…These ROS have been shown to induce CYP1B1 as well [173]. At last, DOX has been shown to provoke a strong inflammatory response which may lead to CYP1B1 induction, particularly through IL-6 and TNFα-mediated signaling [167,174]. Intriguingly, DOX-induced inflammation in the heart of C57Bl/6 mice was sexually dimorphic with stronger inflammatory response in hearts of male mice [19].…”

Gender differences in the susceptibility of hospital-acquired acute kidney injury: more questions than answers

“…Rodents (rats, mice) are genetically similar to humans, and are often used for experimental models of AKI. These animal studies have repeatedly suggested that sexual hormones (testosterone, testosterone/ estrogen ratio, estrogen) are important determinants of sex differences in AKI susceptibility [17][18][19][20][21][22][23]. Female rodents (mice, rats) are much more resistant to ischemic renal injury when compared with male rodents.…”