Examining Effects of Metformin and Coenzyme Q10 on Doxorubicin-Induced Oxidative Hepatotoxicity in Rats

Abstract

Background and purpose: Cancer is considered one of the most common causes of mortality, in today’s world. A growing body of evidence has demonstrated that the global cancer burden is expected to rise significantly in the years to come. Cancer is characterized by the uncontrollable rate of cells growth, ultimately proving fatal if not treated. Both genetic and environmental contributing factors have proven critical in developing differential cancers. Chemotherapy is the most common form of treatment used for cancers all around the world. Despite a high efficiency in treating malignancies, toxicity and targeting of normal healthy tissues are considered the most common side effects of chemotherapeutic agents. Thus, reducing the aforementioned side effects with complementary treatments can prove critical through maximizing therapeutic efficiency while also minimizing unwanted side effects at the same time. Doxorubicin (DOX) is a common chemotherapy drug that, has limitations on its use due to severe side effects such as hepatotoxicity, nephrotoxicity, as well as cardiotoxicity. Metformin is one of the most common drugs originally used for the treatment of type II diabetes. Additionally, coenzyme Q10 is naturally produced by the body and can also be obtained from diet and supplements. Both metformin and coenzyme Q10 have demonstrated protective effects against toxicity and oxidative stress and are attractive candidates for the treatment of diseases with the basis of inflammation and oxidative stress as demonstrated by various studies investigating the effect of metformin as well as coenzyme Q10 against toxicities. This study investigates the protective effects of metformin and coenzyme Q10 alone and in combination against doxorubicin-induced oxidative damage in rats. Materials and methods: In this experiment, 36 male Wistar rats were divided into six groups (n=6). The groups consisted of a normal control group (distilled water), metformin and coenzyme Q10 control group: (metformin+coenzyme Q10), doxorubicin control group (doxorubicin), Metformin pre-treatment group (metformin+ doxorubicin), coenzyme Q10 pre-treatment group (coenzyme Q10+doxorubicin), as well as metformin and coenzyme Q10 pre-treatment group (metformin + coenzyme Q10+doxorubicin). Metformin (200 mg/kg) and coenzyme Q10 (15 mg/kg) were administered orally daily for one week, and doxorubicin (25 mg/kg), was injected on the eighth day. 24 hours after the last injection, blood and liver tissue samples were collected to analyze liver enzymes (i.e. ALT, AST, ALP), oxidative stress parameters (i.e. malondialdehyde, total antioxidant capacity, catalase, superoxide dismutase, glutathione peroxidase), and histological changes. Results: The results showed that doxorubicin significantly elevates the activity of liver enzymes, concentration of malondialdehyde, and tissue damage and decreases total antioxidant capacity, catalase, superoxide dismutase, and glutathione peroxidase activity (P<0.001). Treatment with metformin, coenzyme Q10, and their combination significantly reduced liver enzymes' activity, improved antioxidant parameters, and significantly contributed to histomorphological amelioration compared to the doxorubicin control group. Conclusion: These findings showed that metformin and coenzyme Q10, alone or in combination, can significantly reduce and protect against the liver complications of doxorubicin injection in rats. This effect is likely, through mitigating oxidative stress and bolstering antioxidant defense mechanisms.

Keywords

• doxorubicin
• liver damage
• oxidative stress
• metformin
• coenzyme q10