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

Figures

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  Figure 1. Effect of DOX treatment on the serum level of inflammatory markers. Serum was collected from male or female C57Bl/6 mice 24 h following the administration of a single intraperitoneal injection of 20 mg/kg DOX or saline (n = 8 per group). Inflammatory markers (A) IL-6 and (B) TNF-alpha were measured using the Luminex platform. Data are presented as the mean ± SEM. * p < 0.05, compared to saline-treated mice of the same sex; # p < 0.05, compared to male DOX-treated mice.

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  Figure 2. Effect of DOX treatment on the gene expression of inflammatory markers in the liver. Livers were collected from male or female C57Bl/6 mice 24 h following the administration of a single intraperitoneal injection of 20 mg/kg DOX or saline, and total RNA was isolated (n = 8 per group). Gene expression of (A) IL-6, (B) TNF-alpha, or (C) Cox-2 was determined by real-time PCR. Results were normalized to beta-actin and are expressed relative to the male control. Data are presented as the mean ± SEM. * p < 0.05, compared to control mice of the same sex; # p < 0.05, compared to male DOX-treated mice.

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  Figure 3. Effect of DOX treatment on the gene expression of the Cyp1 family in the liver. Livers were collected from male or female C57Bl/6 mice 24 h (n = 8 per group) or 72 h (n = 4–5 per group) following the administration of a single intraperitoneal injection of 20 mg/kg DOX or saline, and total RNA was isolated. Gene expression of Cyp1a1 was determined by real-time PCR in samples collected (A) 24 or (B) 72 h following DOX treatment. Gene expression of Cyp1b1 in samples collected (C) 24 or (D) 72 h following DOX treatment. Results were normalized to beta-actin and are expressed relative to the male control. Data are presented as the mean ± SEM. * p < 0.05, compared to control mice of the same sex; # p < 0.05, compared to male DOX-treated mice.

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  Figure 4. Effect of DOX treatment on the expression of the Cyp2c sub-family in the liver. Livers were collected from male or female C57Bl/6 mice 24 or 72 h following the administration of a single intraperitoneal injection of 20 mg/kg DOX or saline, and total proteins and RNA were isolated. (A) Gene expression of Cyp2c29 was determined by real-time PCR (n = 8 per group) and (B) protein levels of total Cyp2c were determined by western blotting (n = 4 per group) in samples collected 24 h following DOX treatment. (C) Gene expression of Cyp2c29 (n = 4–5 per group) and (D) protein levels of Cyp2c (n = 4–5 per group) were determined in samples collected 72 h following DOX treatment. PCR results were normalized to beta-actin, and protein expression was normalized to alpha-tubulin. Results of all groups are expressed relative to the male control. Data are presented as the mean ± SEM. * p < 0.05, compared to control mice of the same sex; # p < 0.05, compared to male DOX-treated mice.

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  Figure 5. Effect of DOX treatment on the expression of Cyp2e1 in the liver. Livers were collected from male or female C57Bl/6 mice 24 or 72 h following the administration of a single intraperitoneal injection of 20 mg/kg DOX or saline, and total proteins and RNA were isolated. (A) Gene expression of Cyp2e1 was determined by real-time PCR (n = 8 per group), and (B) protein levels of Cyp2e1 were determined by western blotting (n = 4 per group) in samples collected 24 h following DOX treatment. (C) Gene expression of Cyp2e1 (n = 4–5 per group) and (D) protein levels of Cyp2e1 (n = 4–5 per group) were determined in samples collected 72 h following DOX treatment. PCR results were normalized to beta-actin, and protein expression was normalized to alpha-tubulin. Results of all groups are expressed relative to the male control. Data are presented as the mean ± SEM. * p < 0.05, compared to control mice of the same sex; # p < 0.05, compared to male DOX-treated mice.

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  Figure 6. Effect of DOX treatment on the gene expression of the Cyp4a sub-family in the liver. Livers were collected from male or female C57Bl/6 mice 24 h (n = 8 per group) or 72 h (n = 4–5 per group) following the administration of a single intraperitoneal injection of 20 mg/kg DOX or saline, and total RNA was isolated. Gene expression of Cyp4a10 was determined by real-time PCR in samples collected (A) 24 or (B) 72 h following DOX treatment. Gene expression of Cyp4a12 in samples collected (C) 24 or (D) 72 h following DOX treatment. Results were normalized to beta-actin and are expressed relative to the male control. Data are presented as the mean ± SEM. * p < 0.05, compared to control mice of the same sex; # p < 0.05, compared to male mice of the same treatment.