doi: 10.1111/j.1472-8206.2008.00637.x ORIGINAL ARTICLE Lysosomal abnormalities during benzo(a)pyrene-induced experimental lung carcinogenesis – defensive role of capsaicin P. Anandakumar, S. Kamaraj, S. Jagan, G. Ramakrishnan, T. Devaki* Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India INTRODUCTION N-nitrosamines and polycyclic aromatic hydrocarbons are the two major classes of tobacco-related inhaled carcinogens. The polycyclic aromatic hydrocarbon, viz. benzo(a)pyrene [B(a)P], a potent carcinogen found in tobacco [amount of B(a)P per cigarette is 18–50 ng] [1], is a significant pro-carcinogenic substance, which requires metabolic activation to electrophilic reactive metabolites for its carcinogenic activity [2]. It is well established that B(a)P, after sequential metabolic activa- tion principally by cytochrome P450 1A1 (CYP1A1), generates 7,8-diol-9,10-epoxide-benzo(a)pyrene, which is believed to be the ultimate carcinogenic metabolite of B(a)P [3] that leads to the formation of DNA adducts. Reactive oxygen species (ROS) and organic free-radical intermediates formed from many carcinogens are sug- gested to be involved in the initiation and progression of carcinogenic transformation [4]. B(a)P is a potent carcinogen with a capability to induce enormous amounts of free radicals, which in turn react with lipids causing lipid peroxidation (LPO) [5]. ROS produced by carcinogens are potentially dangerous byproducts of cellular metabolism that have direct effect on cell development, growth and survival. Oxidative stress caused by ROS has been reported in membrane LPO, DNA damage and mutagenesis associated with various stages of tumorigenesis [6]. Capsaicin (CAP) is the chief pungent substance found in hot red and chilli peppers derived from Capsicum fruit extracts. CAP is a unique and effective natural antioxi- dant. It has specificity for free-radical quenching, metal-chelating activity and it also interacts with and regenerates other cellular antioxidants [7]. Apart from this, studies have demonstrated the potent antioxidant property of this compound in counteracting the Keywords benzo(a)pyrene, capsaicin, carbonyl content, lung cancer, lysosomal proteases, oxidative stress Received 27 April 2008; revised 8 July 2008; 8 August 2008; accepted 11 August 2008 *Correspondence and reprints: devakit@yahoo.co.uk ABSTRACT The objective of the present study was to investigate whether lysosome is a target in benzo(a)pyrene-induced, oxidative stress-mediated lung cancer in Swiss albino mice and the plausible role of the phytochemical substance capsaicin in mitigating lysosomal damage. Oxidative stress was assessed based on the level of carbonyl content. The activities of lysosomal proteases like cathepsin-D, cathepsin-B, b-D-glucosidase, b-D-galactosidase, b-D-glucuronidase, b-D-N-acetylglucosaminidase and acid phosphatase were assessed to evaluate lysosomal function. Administration of benzo(a)pyrene (50 mg/kg body weight) to mice induced a increase in the activities of lysosomal enzymes and oxidative stress was evident by the increase in carbonyl content. Treatment with capsaicin (10 mg/kg body weight) decreased carbonyl content and restored the activities of lysosomal enzymes to near normalcy. Transmission electron microscopic study of lysosomes further showed the defensive action of capsaicin against the lysosomal damage caused in benzo(a)pyrene-induced lung cancer. From the present study, it can be concluded that lysosomal damage is an indispensable event in benzo(a)pyrene-induced lung cancer, and capsaicin was able to effectively prevent it, which proves the chemoprotective effect of capsaicin against benzo(a)pyrene-induced experimental lung carcinogenesis. ª 2008 The Authors Journal compilation ª 2008 Socie ´ te ´ Franc ¸aise de Pharmacologie et de The ´ rapeutique Fundamental & Clinical Pharmacology 23 (2009) 97–103 97