Environmental Toxicology and Pharmacology 28 (2009) 11–18 Contents lists available at ScienceDirect Environmental Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/etap Chemopreventive potential of piperine in 7,12-dimethylbenz[a]anthracene- induced skin carcinogenesis in Swiss albino mice Lakshmanan Vellaichamy, Subramanian Balakrishnan, Kuppusamy Panjamurthy, Shanmugam Manoharan ∗ , Linsa Mary Alias Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608002, Tamil Nadu, India article info Article history: Received 9 September 2008 Received in revised form 22 January 2009 Accepted 23 January 2009 Available online 3 February 2009 Keywords: Skin cancer Piperine Lipid peroxidation Antioxidants Detoxification agents abstract The chemopreventive potential of orally administered piperine was studied in Swiss albino mice against 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis. The mechanistic pathway for the chemopreventive potential of piperine was evaluated by analysing the status of phase I and phase II detoxification agents, lipid peroxidation by-products and antioxidants during DMBA-induced skin car- cinogenesis. Skin squamous cell carcinoma was induced in the shaved back of mice, by painting with DMBA (25 g in 0.1ml acetone/mouse) two times weekly for 8 weeks. We observed severe hyperplasia, dysplasia, and well-differentiated squamous cell carcinoma in the 8th, 10th and 15th week of experimen- tal period respectively in mice treated with DMBA alone. Marked alterations in the status of phase I and phase II detoxification agents, lipid peroxidation by-products and antioxidants were observed in tumor bearing mice. Oral administration of piperine (50 mg kg -1 body weight) by gastric gavage significantly prevented the formation of skin tumors during DMBA-induced mouse skin carcinogenesis. Also, piperine administration brought back the status of phase I and phase II detoxification agents, lipid peroxidation by-products and antioxidants to near normal range in DMBA treated mice. The present study thus demon- strates that piperine has significant suppressing effect on cell proliferation during DMBA-induced mouse skin carcinogenesis. The chemopreventive potential of piperine is probably due to its modulating effect on the status of lipid peroxidation, antioxidants and detoxification agents during DMBA-induced skin carcinogenesis. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Skin, the largest organ of the human body, is directly exposed to number of chemical mutagens and carcinogens in a day- to-day life. Skin cancer is one of the most common cancers worldwide and accounts for 30% of all newly diagnosed cancers. More than 1 million skin cancers are diagnosed each year in the United States. Skin cancer accounts for 1–2% of all cancers in India (Deo et al., 2005; Diepgen and Mahler, 2002; Ridky, 2007). 7,12-Dimethylbenz[a]anthracene (DMBA) is commonly employed to induce skin carcinogenesis in mice. DMBA is metabolized to dihydrodiol-epoxide, the ultimate carcinogen, which mediates carcinogenic process by inducing chronic inflammation, over pro- duction of reactive oxygen species (ROS) and oxidative DNA damage (Das and Bhattacharya, 2004). ROS are frequently formed in the biological systems during normal metabolic pathways and as a consequence of exposure to physical, chemical and biological agents. The most important ∗ Corresponding author. Tel.: +91 4144 238343; fax: +91 4144 238080. E-mail address: sakshiman@rediffmail.com (S. Manoharan). ROS in the biological systems include superoxide radicals (O 2 •- ), hydrogen peroxides (H 2 O 2 ), hydroxyl radicals (OH • ), hypochlorous acid (HOCl) and peroxynitrite (ONOO - ). ROS-mediated carcinogen- esis by attacking bases and deoxyribosyl backbone of DNA. Many mutagens and carcinogens exert their carcinogenic effect through generation of excessive ROS (Franco et al., 2008; Das et al., 2004). Profound evidence highlights the crucial role of ROS in the expan- sion and progression of tumors (Valko et al., 2006). ROS-mediated lipid peroxidation has been implicated in the pathogenesis of several disorders including skin cancer (Renju et al., 2007). Peroxidation of membrane lipids may cause impairment in structure and functions of cell membrane (Kolanjiappan et al., 2002). The deleterious effects of ROS are however balanced by the host antioxidant defence system, which includes non-enzymatic antioxidants [vitamin E, C and reduced glutathione (GSH)] and antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)] (Dreher and Junod, 1996). Previ- ous study from our laboratory had demonstrated increased lipid peroxidation and decreased antioxidants in DMBA-induced skin carcinogenesis (Renju et al., 2007). Liver is the primary site for biotransformation of xenobiotics (including carcinogens and anticancer drugs) and detoxification 1382-6689/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.etap.2009.01.008