Modulation of tamoxifen-induced hepatotoxicity by tamoxifen–phospholipid complex Sunil K. Jena a , Sarasija Suresh a and Abhay T. Sangamwar b Departments of a Pharmaceutical Technology (Formulations) and b Pharmaceutics, National Institute of Pharmaceutical Education and Research, SAS Nagar, Punjab, India Keywords antioxidants; hepatotoxicity; reactive oxygen species; tamoxifen; tamoxifen-phospholipid complex Correspondence Abhay T. Sangamwar, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector-67, SAS Nagar, Punjab 160062, India. E-mail: abhays@niper.ac.in Received December 2, 2014 Accepted March 8, 2015 doi: 10.1111/jphp.12422 Abstract Objectives Tamoxifen (TMX), a non-steroidal antiestrogen is a first-line drug in the treatment and prevention of all stages of estrogen-receptor-positive breast cancer. However, oxidative liver damage and hepatocarcinoma are the major problems associated with its long-term clinical use. The aim of this study was to investigate the ameliorative effect of phospholipid against TMX-induced hepatotoxicity. Methods Fifteen female Sprague–Dawley rats were divided into three groups with five rats in each group. Group I received only standard diet and distilled water for 28 days and served as normal. Group II received TMX per day p.o., for 28 days and served as control, and group III received TMX–phospholipid complex (TMX– PLC) per day p.o., for 28 days. Rats were examined for the effect of phospholipid on TMX-induced depletion of antioxidant enzymes, serum biochemical param- eters and induction of lipid peroxidation. Key findings Treatment with TMX–PLC significantly ameliorates the TMX- induced hepatotoxicity by diminishing the toxicity markers such lipid peroxi- dation, aspartate transaminase and alanine transaminase, accompanied by an increase in antioxidant enzyme activity in TMX-treated rats. Histological findings further confirmed the hepatoprotective effect of phospholipid. Conclusions Data of the present study suggests that phospholipid may prove as a useful component of combination therapy in cancer patients under the TMX treatment regimen. Introduction Tamoxifen (TMX), a nonsteroidal ‘antiestrogen’, is used as a first-line drug therapy for the treatment and prevention of all stages of estrogen-receptor-positive breast cancer. [1] TMX is recommended for increased disease-free survival rate and decreased recurrence rate of breast cancer. [2] However, metabolic activation of TMX to electrophilic intermedi- ate(s) by cytochrome P450 mixed function oxidases enzyme in liver (Figure 1) results in the overproduction of reactive oxygen species (ROS), responsible for oxidative liver damage and hepatocarcinoma in rats. [3–6] Hence, long-term clinical use of TMX has been associated with hepatotoxicity. Impaired β-oxidation of fatty acids along with mito- chondrial dysfunction causing steatosis may be the major factors involved in the generation of ROS that leads to the hepatotoxicity. [7] Fatty liver and steatosis are the major problems in more than 30% of breast cancer patient receiv- ing adjuvant TMX treatment. [8] Also, TMX disturbs the intramitochondrial calcium [Ca 2+ ]m homeostasis by shifting the mitochondrial non-ionised/ionised calcium equilibrium towards the ionised form. As a result, elevated [Ca 2+ ]m stimulates mitochondrial nitric oxide synthase that increases the intramitochondrial peroxynitrite level and subsequently induce oxidative stress and mitochondrial apoptosis. [9] Several studies report the beneficial effect of phospholip- ids in tumour and metastasis inhibition. [10] Phospholipids are the principle component of all cellular and subcellular membranes. Phosphatidylcholine, also known as lecithin, is the most abundant phospholipid in animals and plants, and in addition, a principle phospholipid circulating in the And Pharmacology Journal of Pharmacy Research Paper © 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 1198–1206 1198 Downloaded from https://academic.oup.com/jpp/article/67/9/1198/6128244 by guest on 31 December 2022