Reduction of Mitochondrial Oxidative Damage and Improved Mitochondrial Efficiency by Administration of Crocetin against Benzo[a]pyrene Induced Experimental Animals

Abstract

The polycyclic aromatic hydrocarbon benzo [a]pyrene (B[a]p), was first isolated from coal tar and characterized by Cook et al. 1) B[a]p is one of the most prevalent environmental carcinogens to which humans are exposed. B [a]p is a very effective carcinogen which interacts with membrane lipids and consequently induces free radical formation.2) B[a]p activates oxidative stress especially lipid peroxidation, which is known to be involved in carcinogenesis.3) B[a]p activates oxidative stress-induces cell proliferation and carcinogenesis by transcriptional elevation of several genes including Campus c-jun, c-fos, c-myc and inducible nitric oxide synthase (iNOS). These genes are found to be activated by stress signal through the stimulation of tyrosine kinase, which in turn modulates down stream events including the expression of nuclear proto oncogenes. 4)Reactive oxygen species (ROS) are broadly defined as oxygen-containing chemical species with reactive chemical properties, which includes free radicals such as superoxide (O 2 Ϫ ) and hydroxyl radicals (HO˙), that contains an unpaired electron, and non-radical molecules such hydrogen peroxide (H 2 O 2 ). ROS are constantly generated and eliminated in the biological system, and play important roles in a variety of normal biochemical functions and abnormal pathological processes. Growing evidence suggests that cancer cells exhibit increased intrinsic ROS stress, due to in part with oncogenic stimulation and increased metabolic activity. 5)Antioxidants are molecules that prevent or inhibit the oxidation process mediated by ROS. In addition to many small antioxidant molecules, there are many antioxidant proteins in vivo. Superoxide dismutase (SOD) is one of the primary antioxidant enzymes. This family of enzymes catalyzes the dismutation of O 2 to H 2 O 2 . Hydrogen peroxide is further detoxified to water by catalase and glutathione peroxidase. There are three isoforms of SOD in human cells: copper-zinc SOD, found predominantly in the cytoplasm; extracellular SOD; and MnSOD, which exists primarily in the mitochondrial matrix.Mitochondrial inner membrane is impermeable to all molecules including charged ions. The complex process of ATP synthesis occurs at the inner mitochondrial membrane through the donation of electrons by nicotinamide adenine dinucleotide (NAD) or flavine adenine dinucleotide (FAD) equivalents generated by the tricarboxylic acid (TCA) cycle. These electrons passes along a series of molecular complexes known as the electron transport system. Simultaneously, protons are transferred across the inner membrane at complexes I, III and IV to establish a trans-membrane gradient of electrical charge known as the membrane potential. 6)The enhanced susceptibility of membrane to LPO can lead to loss of adenosine triphosphatases (ATPases) activity and changes in cell functions. 7) ATPases are lipid dependent membrane bound enzymes, which are involved in active transport, of ions inside and outside of mitochondria thereby properly maintaining the electrical and c...

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