Sexual dimorphism in doxorubicin‐induced systemic inflammation: Implications for hepatic cytochrome p450 regulation

Marianne K.o. Grant; Ibrahim Y. Abdelgawad; Christine A. Lewis; Beshay N. Zordoky

doi:10.3390/ijms21041279

Sexual dimorphism in doxorubicin‐induced systemic inflammation: Implications for hepatic cytochrome p450 regulation

Marianne K.o. Grant, Ibrahim Y. Abdelgawad, Christine A. Lewis, Beshay N. Zordoky

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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.

Original language	English (US)
Article number	1279
Journal	International journal of molecular sciences
Volume	21
Issue number	4
DOIs	https://doi.org/10.3390/ijms21041279 https://doi.org/10.3390/ijms21041279
State	Published - Feb 2 2020

Bibliographical note

Funding Information:
Beshay N. Zordoky is a Masonic Cancer Center Women’s Health Scholar, sponsored by the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute and administered by the University of Minnesota Women’s Health Research Program. This research was supported by a research grant from the Rally Foundation for Childhood Cancer (Award ID 582420) and by the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences, Experiments using the NanoDrop 8000, ABI 7900 HT, and Agilent 2100 Bioanalyzer were done with staff support at the University of Minnesota Genomics Center. Experiments using the Amersham Imager 600UV were done with staff support at the University of Minnesota Imaging Center. Experiments using the Luminex platform were done with staff support at the University of Minnesota Cytokine Reference Laboratory.

Funding Information:
Funding: Beshay N. Zordoky is a Masonic Cancer Center Women’s Health Scholar, sponsored by the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute and administered by the University of Minnesota Women’s Health Research Program. This research was supported by a research grant from the Rally Foundation for Childhood Cancer (Award ID 582420) and by the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences,

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Cytochrome P450
Doxorubicin
Inflammation
Liver
Sexual dimorphism

PubMed: MeSH publication types

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title = "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.",

keywords = "Cytochrome P450, Doxorubicin, Inflammation, Liver, Sexual dimorphism",

author = "Grant, {Marianne K.o.} and Abdelgawad, {Ibrahim Y.} and Lewis, {Christine A.} and Zordoky, {Beshay N.}",

note = "Funding Information: Beshay N. Zordoky is a Masonic Cancer Center Women{\textquoteright}s Health Scholar, sponsored by the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute and administered by the University of Minnesota Women{\textquoteright}s Health Research Program. This research was supported by a research grant from the Rally Foundation for Childhood Cancer (Award ID 582420) and by the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences, Experiments using the NanoDrop 8000, ABI 7900 HT, and Agilent 2100 Bioanalyzer were done with staff support at the University of Minnesota Genomics Center. Experiments using the Amersham Imager 600UV were done with staff support at the University of Minnesota Imaging Center. Experiments using the Luminex platform were done with staff support at the University of Minnesota Cytokine Reference Laboratory. Funding Information: Funding: Beshay N. Zordoky is a Masonic Cancer Center Women{\textquoteright}s Health Scholar, sponsored by the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute and administered by the University of Minnesota Women{\textquoteright}s Health Research Program. This research was supported by a research grant from the Rally Foundation for Childhood Cancer (Award ID 582420) and by the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences, Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

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N2 - 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.

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Sexual dimorphism in doxorubicin‐induced systemic inflammation: Implications for hepatic cytochrome p450 regulation

Abstract

Bibliographical note

Keywords

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Amersham Imager 600UV

Molecular Biology Imagers

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Sexual dimorphism in doxorubicin‐induced systemic inflammation: Implications for hepatic cytochrome p450 regulation

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

Access

OpenUrl availability

Other files and links

Fingerprint

Equipment

Amersham Imager 600UV

Molecular Biology Imagers

University Imaging Centers

Cite this