Abstract
Most of the exogenous and endogenous chemical compounds are metabolized by enzymes of xenobiotic processing pathways, including the phase I cytochrome p450 species. Carcinogens and their metabolites are generally detoxified by phase II enzymes like glutathione-S-transferases (GST). The balance of enzymes determines whether metabolic activation of pro-carcinogens or inactivation of carcinogens occurs. Under certain conditions, deregulated expression of xenobiotic enzymes may also convert endogenous substrates to metabolites that can facilitate DNA adduct formation and ultimately lead to cancer development. In this study, we aimed to test the association between deregulation of metabolizing genes and brain tumorigenesis. The expression profile of metabolizing genes CYP1A1 and GSTP1 was therefore studied in a cohort of 36 brain tumor patients and controls using Western blotting. In a second part of the study we analyzed protein expression of GSTs in the same study cohort by ELISA. CYP1A1 expression was found to be significantly high (p<0.001) in brain tumor as compared to the normal tissues, with ~4 fold (OR=4, 95%CI=0.43-37) increase in some cases. In contrast, the expression of GSTP1 was found to be significantly low in brain tumor tissues as compared to the controls (p<0.02). This down regulation was significantly higher (OR=0.05, 95%CI=0.006-0.51; p<0.007) in certain grades of lesions. Furthermore, GSTs levels were significantly down-regulated (p<0.014) in brain tumor patients compared to controls. Statistically significant decrease in GST levels was observed in the more advanced lesions (III-IV, p<0.005) as compared to the early tissue grades (I-II). Thus, altered expression of these xenobiotic metabolizing genes may be involved in brain tumor development in Pakistani population. Investigation of expression of these genes may provide information not only for the prediction of individual cancer risk but also for the prevention of cancer.
Highlights
Brain tumor is a solid neoplasm that arises within the brain, inside the cranium or in the central spinal canal
Phase II metabolizing enzymes such as GSTP1 play an important role in biotransformation of endogenous compounds and xenobiotics to more excretable forms as well as in the metabolic inactivation of active compounds making them water soluble (Jancova et al, 2010; Nosheen et al, 2011)
Our study found significant up regulation of CYP1A1
Summary
Brain tumor is a solid neoplasm that arises within the brain, inside the cranium or in the central spinal canal. Certain relatively more lipophilic xenobiotics can diffuse through the endothelial cells of the brain capillaries and penetrate into the brain (Liu et al, 2004). Improper metabolism of these lipophilic xenobiotics results in carcinogenesis in brain region (Chang et al, 2005). A wide variety of enzymes provide protection from harmful injury by toxic chemicals (Thomas and Manfred, 2005). Among these enzymes, Glutathione-S-transferase (GST) is important for detoxifying exogenous and endogenous substances and protecting cells from the toxic effects of ROS (Narasimhan et al, 2011; Yao et al, 2012). The main function of these enzymes is to catalyze the formation of glutathione-S-conjugates with electrophiles, which is crucial for inactivation and subsequent excretion of these molecules (Koh et al, 2011; Nosheen et al, 2011)
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