Elsevier

Life Sciences

Volume 250, 1 June 2020, 117599
Life Sciences

Review article
New molecular and biochemical insights of doxorubicin-induced hepatotoxicity

https://doi.org/10.1016/j.lfs.2020.117599Get rights and content

Abstract

Chemotherapeutic antibiotic doxorubicin belongs to the anthracycline class, slaughters not only the cancer cells but also non-cancerous cells even in the non-targeted organs thereby resulting in the toxicity. The liver is primarily involved in the process of detoxification and this mini-review we focused mainly to investigate the molecular mechanisms heading hepatotoxicity caused due to doxorubicin administration. The alterations in the doxorubicin treated liver tissue include vacuolation of hepatocytes, degeneration of hepatocyte cords, bile duct hyperplasia and focal necrosis. About the literature conducted, hepatotoxicity caused by doxorubicin has been explained by estimating the levels of liver serum biomarkers, ROS production, antioxidant enzymes, lipid peroxidation, and mitochondrial dysfunction. The liver serum biomarkers such as ALT and AST, elated levels of free radicals inducing oxidative stress characterized by a surge in Nrf-2, FOXO-1 and HO-1 genes and diminution of anti-oxidant activity characterized by a decline in SOD, GPx, and CAT genes. The augmented levels of SGOT, SGPT, LDH, creatine kinase, direct and total bilirubin levels also reveal the toxicity in the hepatic tissue due to doxorubicin treatment. The molecular insight of hepatotoxicity is mainly due to the production of ROS, ameliorated oxidative stress and inflammation, deteriorated mitochondrial production and functioning, and enhanced apoptosis. Certain substances such as extracts from medicinal plants, natural products, and chemical substances have been shown to produce an alleviating effect against the doxorubicin-induced hepatotoxicity are also discussed.

Introduction

Cancer is one of the deadliest diseases with an exponential mortality rate among the worldwide population [1]. Doxorubicin belongs to anthracyclines class of compounds and is widely used as a chemotherapeutic drug to treat various types of cancers such as lymphomas, leukemias, and carcinomas of the breast, ovaries, thyroid, lungs [[2], [3], [4]]. A red-colored pigment extracted from the Streptococcus peucetius strain produced an antibiotic against tumors in mice known as daunorubicin. This streptococcus species was further genetically manipulated to produce adriamycin, also called as doxorubicin. Doxorubicin possesses a broad spectrum of therapeutic index [3]. Doxorubicin is marketed under the brand name adriamycin which is available in both powdered and liquid form and typically administered through intravenous route in doses of 60 to 75 mg/m2 body surface area every 21 to 28 days. It is also available in liposomal form [5]. Apart from its chemotherapeutic activity, the traditional usage of doxorubicin has been limited due to its adverse effects on various organs which led to cardiotoxicity, hepatotoxicity, nephrotoxicity, fertility problems and induction of type-2-diabetes like condition, diabetic cardiomyopathy [[6], [7], [8]]. Due to its biphasic nature doxorubicin has been shown to induce hepatotoxicity at acute and sub-acute doses [9]. The molecular mechanisms involved in doxorubicin causing hepatotoxicity are mainly due to the production of reactive oxygen species (ROS) by the drug during its metabolism in the liver which results in imbalanced redox potential leading to oxidative stress, reduced levels of antioxidant enzymes, apoptosis, inflammation, and mitochondrial dysfunction. The liver is the major organ involved in the process of metabolism and detoxification of drugs. Doxorubicin can be administered directly or in the pegylated form called as doxorubicin hydrochloride (Caelyx) where the drug is encapsulated inside the liposomes whose surface is bounded with methoxy-polyethylene glycol groups thereby resulting in the targeted delivery to tumor sites to some extent, escaping the immunosurveillance, promoting the sustained release of drug for a longer time, and reduced drug content in the hepatic tissue [10,11]. The major advantage behind the liposomal formulation is it reduces the drug-induced toxicity to other healthy or non-targeted tissues whereas the liposomal form of the drug is restricted to undergo hepatic metabolism due to the size of the fenestrations present on the hepatic sinusoidal endothelium which acts as a barrier stands as a disadvantage thereby indicating reduced clearance and volume of distribution [11].

Section snippets

Doxorubicin - mechanism of action

The doxorubicin intercalates between nitrogenous bases of DNA and inhibits the biosynthesis of macromolecules [12,13] which in turn leads to inhibition in the activity of topoisomerase II (Top II) enzyme due to which the replication process is disrupted. Thus, cancerous cells are ceased from cell division [1]. An enzymatic method, the doxorubicin undergoes a reversible oxidation process and produces a semiquinone form as an intermediate, catalyzed by the enzyme Nicotinamide adenine dinucleotide

Structural abnormalities in doxorubicin treated liver

Various reports were produced based on structural examination of liver tissue extracted from animal models treated with doxorubicin. The histopathological examination of hepatic tissue after doxorubicin treatment revealed marked bile duct hyperplasia, dilation of sinusoidal space, and central vein congestion [23], vacuolation of hepatocytes, dilatation of sinusoids, condensation of nuclei and degeneration of hepatocyte cords [24], cellular edema, focal necrosis, and de-arrangement of hepatic

Molecular and biochemical alterations in the liver upon doxorubicin treatment

Biochemical examination of doxorubicin treatment reported a significant increase in levels of Alanine Transaminase (ALT) and Aspartate Transaminase (AST) indicating damage to hepatic tissue is reported in different studies [[29], [30], [31]]. Doxorubicin possesses the ability to produce superoxide radicals and peroxynitrite radicals during its metabolism in the liver. Therefore, the ROS produced initiates lipid peroxidation which results in hepatic damage and leakage of the hepatic enzymes such

Molecular mechanisms involved in doxorubicin-induced hepatotoxicity

The molecular mechanisms behind the doxorubicin hepatotoxicity and the dosage of the drugs administered are mentioned in Table 1. The elevated ALT, AST and GGT levels in the serum are a prime indicator for hepatic damage. Investigating into the molecular insights that doxorubicin-induced hepatic damage is initiated upon the activation of genes responsible for oxidative stress response, DNA damage, DNA repair, drug transport, a progression of the cell cycle, mitochondrial dysfunction and

Amelioration of doxorubicin-induced hepatotoxicity via natural products and chemicals

Many reports have been published regarding the alleviating effect of certain substances against the hepatotoxicity induced by the anthracycline antibiotic drug doxorubicin. Various types of natural products and certain drugs have shown to produce a hepatoprotective effect eliminating the toxic effect of doxorubicin. Natural extracts from plants such as Acetyl-11-keto beta boswellic acid is a pentacyclic triterpenoid extracted from Boswellia serrata which possess antioxidant and

Conclusion

Eventually, we conclude that anthracycline antibiotic doxorubicin confers toxicity to hepatic tissue which was proved by many scientific reports. The main reason underlying doxorubicin-induced hepatotoxicity is the production of free radicals in the off-target tissues. The incentives regarding the toxicity are oxidative stress, inflammation, and apoptosis due to ROS production, mitochondrial dysfunction causing imbalanced energy status in the cell eventually leading to apoptosis. The oxidative

Funding

The authors thank VIT for providing “VIT SEED GRANT” for carrying out this work.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The author Kaviyarasi Renu is grateful to ICMR for providing financial assistance during this tenure. The authors thank VIT, Vellore, Tamilnadu, India, for supporting this work.

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