Elsevier

Food and Chemical Toxicology

Volume 48, Issues 8–9, August–September 2010, Pages 2052-2058
Food and Chemical Toxicology

Ameliorative effect of riboflavin on the cisplatin induced nephrotoxicity and hepatotoxicity under photoillumination

https://doi.org/10.1016/j.fct.2010.05.004Get rights and content

Abstract

Cisplatin is a widely used anticancer drug. It is documented that it elicits major side effects like nephrotoxicity and hepatotoxicity due to oxidative stress forcing the patients to limit its clinical use in long term treatment. Riboflavin (vitamin B2) is a strong photosensitizer because it generates reactive oxygen species (ROS) upon photoillumination. We have tried to trap its photosensitizing property to ameliorate the cisplatin induced nephrotoxicity and hepatotoxicity in mice. They were treated with riboflavin and cisplatin separately as well as with their combination under photoilluminated condition. The status of major antioxidant enzymes, antioxidant proteins, functional markers, lipid peroxidation and protein oxidation was studied in liver, kidneys and serum samples of all the groups. Cisplatin treated group showed significantly compromised level of antioxidant enzymes and the proteins with higher extent of lipid and protein oxidation. Similar but less pronounced pattern was observed in the riboflavin treated group. The groups treated with the combination of cisplatin and riboflavin showed all the parameters tended towards normal levels in a dose dependent manner. Hence, it can be hypothesized that riboflavin shows ameliorative effect on the cisplatin induced nephrotoxicity and hepatotoxicity under the mentioned treatment conditions.

Introduction

Cisplatin (cis-diamminedichloroplatinum II, CIS) is platinum coordinated complex based anticancer drug used against many human cancers including oral, lung, head and neck cancer, metastatic tumors of testis and ovaries, advanced bladder cancer and many other solid tumors (Gottfried et al., 2008, Turk et al., 2008). In spite of its effective anticancer behavior, it exerts many unwanted side effects including nephrotoxicity, hepatotoxicity, ototoxicity, emetogenesis myelosuppression and spermiotoxicity (Tarladacalisir et al., 2008, Liao et al., 2008, Atessahin et al., 2006, Mc Keage, 1995). Hence, these major side effects limit the clinical use of the drug.

The anticancer property of CIS comes from its ability to bind to N-7 of purine bases of cellular DNA leading to formation of mono-adducts which are later transformed into inter- and intra-strand cross links by reaction of second reactive site of the drug with the second nucleobase (Hah et al., 2006, Fichtinger-Schepman et al., 1985). This is inhibitory to fundamental cellular processes including replication, transcription, translation and DNA-repair in many cell types (Suo et al., 1999). Beside these, CIS generates oxidative and nitrosative stresses (Srivastava et al., 1996, Xiao et al., 2003) because of depletion or inhibition of antioxidant enzymes and proteins which results into nephrotoxicity and hepatotoxicity as major side effects of the drug (Iseri et al., 2007, Naziroglu et al., 2004).

Riboflavin (RF) or vitamin B2 is chemically 6,7-dimethyl-9-d-1-ribityl isoalloxazine. It is a natural constituent of all forms of life, exists in the two co-enzymatic forms – flavinadenine dinucleotide (FAD) and flavinadenine mononucleotide (FMN) that are used in metabolic redox reaction by different enzyme-systems. It also acts as photosensitizer via radical species or via the generation of singlet oxygen. It reacts via its singlet and triplet excited states with molecular oxygen leading to generation of superoxide anion, riboflavin radical (Kumari et al., 1996) and generates hydroxyl radical in presence of transition metal ions (Yoshida et al., 2003). These species exert a collective damaging effect on several biologically important molecules (Jazzer and Naseem, 1994, Jazzer and Naseem, 1996) and can also affect the drugs as well as the medicines (Cosa, 2004). Apart from being an essential vitamin, its photosensitizing property makes it an effective agent for photodynamic therapy in killing tumors (Edwards et al., 1994), inactivation of neurotoxin A (Eubanks et al., 2005), treatment of neonatal hyperbilirubinemia, blue nevi, pigmented skin lesions (Sato et al., 2000) and sterilization of blood products (Cui et al., 2008). The present study was designed to enlarge the therapeutic window of RF to regulate the nephrotoxic and hepatotoxic effects of CIS in mice as animal model system. It is a preliminary attempt to suggest alternative regime for the cancer patients undergoing CIS based chemotherapy based on our earlier in vitro observation.

Section snippets

Chemicals

Riboflavin, cisplatin, reduced and oxidized glutathione, nicotinamide adenine dinucleotide phosphate reduced (NADPH), nicotinamide adenine dinucleotide reduced (NADH) were bought from Sigma–Aldrich Chemical Company, USA. Succinic acid, potassium dihydrogen and monohydrogen phosphate, glycine, pyrogallol, hydrogen peroxide, trichloroacetic acid (TCA) and ethylenediaminetetra-acetic acid (EDTA) were purchased from Qualigens Fine Chemicals, Mumbai, India. Folin’s phenol reagent, bovine serum

Results

The animals were given 8 intraperitoneal doses of the treatment. They were sacrificed all together on the same day. Major target organs of the treatment – kidney and liver and the blood of all mice were collected. Their organs were homogenized and blood was centrifuged to get the supernatants and the serums, respectively, at −4 °C and was stored at −20 °C after that. Their biochemical study and analysis were carried-out to see whether the groups fifth and sixth showed any recovery or healing from

Discussion

Cisplatin (CIS) is one of the most widely used anticancer drug for the treatment of various cancers and solid tumors (Sweetman, 2002). However, its major side effects – nephrotoxicity and hepatotoxicity are the main limiting factors of its clinical use for long term treatment (Antunes et al., 2000, Zicca et al., 2002). Various treatment-strategies and curing agents have been tried and used to monitor or control its side effects since its discovery. Earlier studies from our lab have shown that

Conclusion

It may be hypothesized that the excitable electrons in alloxazine ring of RF may interact with the active groups of CIS at the molecular level which may possibly lead to decreased production of ROS by CIS thereby reducing the oxidative stress as well as suppressing the riboflavin prooxidant potential leading to decreased ROS generation in the target organs and correspondingly improved status of the organs effected by CIS toxicity. Hence, our work opens a novel window to manage CIS-induced

Conflict of Interest

The authors declare that there are no conflicts of interest.

Acknowledgements

The authors acknowledge the financial assistance provided by the University Grant Commission (UGC), New Delhi under SAP program, DST-FIST and the facilities provided by the Department of Biochemistry, Aligarh Muslim University. We are also thankful to Prof. Riyaz Mahmood, Dr. Shams Tabrez, all the friends, lab colleagues and the fellows who directly or indirectly helped us during different phases of treatment and experimentation in this work.

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