Review articleNew molecular and biochemical insights of doxorubicin-induced hepatotoxicity
Graphical abstract
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.
References (73)
- et al.
Deciphering the molecular mechanism during doxorubicin-mediated oxidative stress, apoptosis through Nrf2 and PGC-1α in a rat testicular milieu
Reprod. Biol.
(2019) - et al.
Elevated lipolysis in adipose tissue by doxorubicin via PPARα activation associated with hepatic steatosis and insulin resistance
Eur. J. Pharmacol.
(2019) - et al.
Molecular mechanism of doxorubicin-induced cardiomyopathy–an update
Eur. J. Pharmacol.
(2018) - et al.
The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity
Toxicol. Appl. Pharmacol.
(2012) - et al.
Superoxide and hydrogen peroxide production and NADPH oxidation stimulated by nitrofurantoin in lung microsomes: possible implications for toxicity
Life Sci.
(1979) - et al.
Antioxidant nutrients and adriamycin toxicity
Toxicology
(2002) - et al.
Oxidant-antioxidant status in patients with oral squamous cell carcinomas at different intraoral sites
Clin. Biochem.
(2002) - et al.
Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide
Free Radic. Biol. Med.
(1998) - et al.
Biological aspects of reactive nitrogen species
Biochim. Biophys. Acta
(1999) - et al.
Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats
Arch. Med. Res.
(2007)
Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats: the effects of vitamin E and catechin
Toxicology
Theanine prevents doxorubicin-induced acute hepatotoxicity by reducing intrinsic apoptotic response
Food Chem. Toxicol.
The selective effect of cystathionine on doxorubicin hepatotoxicity in tumor-bearing mice
Eur. J. Pharmacol.
Oxidative stress induced in rat liver by anticancer drugs doxorubicin, paclitaxel and docetaxel
Adv. Med. Sci.
Adriamycin-induced hepatic and myocardial lipid peroxidation and DNA damage, and enhanced excretion of urinary lipid metabolites in rats
Toxicology
Potential hepatoprotective effects of fullerenol C60 (OH) 24 in doxorubicin-induced hepatotoxicity in rats with mammary carcinomas
Biomaterials
What is oxidative stress?
Metabolism-Clinical and Experimental
Heme oxygenase-1 protein localizes to the nucleus and activates transcription factors important in oxidative stress
J. Biol. Chem.
The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems
Exp. Cell Res.
Effect of the oxidative stress induced by adriamycin on rat hepatocyte bioenergetics during ageing
Mech. Ageing Dev.
Curcumin enhanced adriamycin-induced human liver-derived Hepatoma G2 cell death through activation of mitochondria-mediated apoptosis and autophagy
Eur. J. Pharm. Sci.
Physical exercise positively modulates DOX-induced hepatic oxidative stress, mitochondrial dysfunction and quality control signaling
Mitochondrion
Dioscin, a natural steroid saponin, induces apoptosis and DNA damage through reactive oxygen species: a potential new drug for treatment of glioblastoma multiforme
Food Chem. Toxicol.
Antioxidant role of catechin in health and disease
Protective mechanisms of atorvastatin against doxorubicin-induced hepato-renal toxicity
Biomed. Pharmacother.
An overview of doxorubicin formulations in cancer therapy
J. Cancer Res. Ther.
Doxorubicin pathways: pharmacodynamics and adverse effects
Pharmacogenet. Genomics
Adriamycin, 14-Hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius
Biotechnol. Bioeng.
Role of anthracyclines in the era of targeted therapy
Cardiovasc. Toxicol.
Livertox: Clinical And Research Information on Drug-induced Liver Injury
Pharmacokinetics of pegylated liposomal doxorubicin
Clin. Pharmacokinet.
The hepatic pharmacokinetics of doxorubicin and liposomal doxorubicin
Drug Metab. Disposition.
Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells
Mol. Pharmacol.
Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells
Cancer Res.
Role of hydrogen peroxide and hydroxyl radical formation in the killing of Ehrlich tumor cells by anticancer quinones
Proc. Natl. Acad. Sci. U. S. A.
Nitric oxide and cancer: a review
World J. Surg. Oncol.
Cited by (137)
Novel naphthoquinone-1H-1,2,3-triazole hybrids: Design, synthesis and evaluation as inductors of ROS-mediated apoptosis in the MCF-7 cells
2024, Bioorganic and Medicinal ChemistryThe mechanistic interplay between Nrf-2, NF-κB/MAPK, caspase-dependent apoptosis, and autophagy in the hepatoprotective effects of Sophorolipids produced by microbial conversion of banana peels using Saccharomyces cerevisiae against doxorubicin-induced hepatotoxicity in rats
2023, Food and Chemical ToxicologyStudy of the effect of bezafibrate with ginkgo biloba extracts in an animal model of hepatotoxicity induced by doxorubicin
2023, Biochemistry and Biophysics ReportsAngiotensin IV ameliorates doxorubicin-induced cardiotoxicity by increasing glutathione peroxidase 4 and alleviating ferroptosis
2023, Toxicology and Applied PharmacologyN-Acetylcysteine may exert hepatoprotective effect by regulating Meteorin-Like levels in Adriamycin-induced liver injury
2023, Cell Stress and Chaperones
- $
Equal Contribution for first authors.