Triangulación en el proceso y en los resultados de la evaluación

Omega 3 fatty acids are PolyUnsaturated Fatty Acids (PUFAs) with a double bond at the third carbon atom. The fatty acids have two ends with carboxylic acid (COOH) on one end and methyl group on the other end as shown in Figures 2.6 and 2.7. The carboxylic end is considered as the beginning of the fatty acid chain, whereas the methyl end is the tail. Since omega 3 fatty acids have a double bond at the third carbon from the methyl end (ω end) they are named as omega 3 fatty acids. DHA and EPA are selected for the current study from the group of omega 3 fatty acids. They were selected because they are chemically active and play an important role in pharmacology due to their health significance.

PPAR RXR RAR L OX FXR SXR

Tocotrienol

49 Figure 2.6 Structure of DHA

Figure 2.7 Structure of EPA

DHA has 6 double bonds with 22 carbon atoms as shown in Figure 2.6, whereas EPA has 5 double bonds with 20 carbon atoms (Figure 2.7). The first double bond in both DHA and EPA starts at the third carbon from the methyl or ω end.

2.3.2.1.

Metabolism of DHA and EPA

Omega 3 fatty acids as such are not produced in the body and hence must be supplied through diet. Fish oil is rich in both DHA and EPA. It was not much known about the metabolism of

50 DHA and EPA in the body (Li et al., 2005). It was found in a study that EPA can get incorporated into phospholipid bilayer (Hawcroft et al., 2010). Further, in phospholipid bilayer EPA competes with the active site of COX-2 enzyme. After activating COX-2, EPA metabolizes into prostaglandin-E3 and acts efficiently in reducing human lung and pancreatic cancer (Funahashi et al., 2008; Yang et al., 2004). Consumption of fish oil rich in DHA and EPA was identified to improve the prognosis of diseases such as atherosclerosis, psoriasis and rheumatoid arthritis (Clark et al., 1993; Simopoulos, 2002).

2.3.2.2. Biological Activity of Omega 3 Fatty Acids

The medical importance of DHA and EPA along with a few antirheumatic drugs and other drugs have been shown to be effective in treating diseases like ulcerative colitis, hyperlipidemia, and skin lesions and also in decreasing the toxicity of cyclosporine in patients with psoriasis (Simopoulos, 1991). Moreover, omega 3 fatty acids are required for the normal functional development of the retina and brain, predominantly in premature infants (Simopoulos, 1991). They also help in preventing cancer by arresting the cell cycle and inducing apoptosis by activating phosphatase (Rafat et al., 2004). Omega 3 fatty acids have also been suggested to play an important role in the pathophysiology and treatment of bipolar disorder (Stoll et al., 1999). Animal studies suggest that omega 3 fatty acids exert protective effects against breast, colon and prostate cancers. In patients with colorectal cancer DHA and EPA decrease cell proliferation and maintain the balance between colonic cell proliferation and apoptosis (Simopoulos, 2003). Among the fatty acids, omega 3 fatty acids possess most potent immunomodulatory activities and among omega 3 fatty acids DHA and EPA are biologically more potent (Simopoulos, 2002). Animal experiments and clinical intervention indicate that because of anti-inflammatory properties omega 3 fatty acids can be used in the treatment of autoimmune diseases (Simopoulos, 2002). The UK dietary guidelines for cardiovascular diseases acknowledge the importance of long-chain omega-3 fatty acids in

51 reducing the risk of heart diseases (Ruxton et al., 2004). The deficiency of omega 3 fatty acids in a normal diet leads to harmful effects on synaptic functions and emotional behaviour (Lafourcade et al., 2011).

2.3.2.2. Interactions of Omega 3 Fatty Acids with Different Proteins

Computational docking and molecular simulation studies performed in the previous research indicated that DHA binds to PPARs and RXRs with high affinity (Gani & Style, 2008). Unfortunately, there is no experimental evidence for the binding of DHA with PPAR (Gani & Style, 2008). Due to high affinity, EPA occupies the ligand binding pocket of PPAR (Xu et al., 1999). DHA and EPA activate the cannabinoid receptors and express their endocannabinoid’s nature (Brown et al., 2010). DHA and EPA are the novel ligands of transient receptor potential vanilloid receptor (TRPV1) which is an ion channel expressed in neurons and brain (Lafourcade et al., 2011).

The beneficial health effects of DHA and EPA relate to their anti-inflammatory properties, the exact mechanism is unknown (Balvers et al., 2010). The mechanism behind the binding of omega 3 fatty acids to G protein-coupled receptor 120 (GPR120) is also not clear, however, it results in broad anti-inflammatory effects (Oh et al., 2010). Platelet aggregation is caused by the interaction of Cyclooxygenase (COX) with omega 3 fatty acids (Hu et al., 2002). The beneficial effects on lipid metabolism are because of the selective regulation of FXR caused by the binding of omega 3 fatty acids to FXR (Zhao et al., 2004). The binding of RAR with omega 3 fatty acids result in the expression of genes involved in synaptic plasticity (Buaud et al., 2010).

The target targets and enzymes were predicted from the literature review and are shown in Figure 2.8. The research done so far on omega 3 fatty acids suggests that they could be the potential drug candidates to design drugs for diseases like cancer, heart diseases and

52

Omega 3 fatty acids

FXR PPAR RXR CB1 RAR COX ARA CB2 T R P V1 GPR1 20

behavioural disorders. The interaction of DHA and EPA with different biological proteins is significant and needs to be further tested.