Yang et al. (2007), Arachidonic Acid
August 2008, model of the month by Dominic P. Tolle
Flux analysis (Figure 2A) shows that the first 5 min are important for the flux through the 5LOX pathway and production of LTs. Following the initial phase, the flux through the 5LOX pathway is shut off by negative feedback and the flux through the 15LOX pathway becomes dominant. Simulations of COX2 inhibition (Figure 2B), 5LOX inhibition (Figure 2C) and a combination (Figure 2D) of both are also shown, and let the authors argue that a combination of inhibition of the 5LOX and COX2 branch would give more effective therapeutic results. Figure 2. Flux analysis of the three main pathways: 5LOX (red), 15LOX (blue) and COX2 (green). No inhibitors (A); COX2 inhibitor (B); 5LOX inhibitor (C); both inhibitors (D). After [3]. To further analyse the pharmacological effects of inhibiting the 5LOX branch and the COX branch, two strategies were simulated: dual function inhibitors and a mix of two types of inhibitors, one for each enzyme. The potency of these two strategies is dependent on two related concepts: the relative inhibition constant to different enzymes (DR) for the dual function inhibitor and the mixing ratio (MR) for the mixture of two types of inhibitors. The inhibition intensity (I) on the production of LTs and PGs was calculated to evaluate the efficacy of inhibition for the dualfunction inhibitor and the mixture of inhibitors. Both, effect of relative inhibitor/enzyme concentrations and the ratio of DR/MR value to relative activity of the two enzymes (ER) was investigated (Figure 3). The dualfunction inhibitor and the inhibitor mixture both had the largest effective concentration region when the DR/MR value was close to the ER of the two enzymes, however the dualfunction inhibitor was more effective than the mixture of inhibitors at low concentrations. Figure 3. Effect of mixture and dualfunction COX2/5LOX Inhibitors. Mixture of two inhibitors (A); Dualfunction inhibitor (B); Comparison of two inhibitor strategies (C). After [3] Many of the pharmaceutical industries most successful drugs act on the AA metabolic network. The model of Yang et al. describes the dynamics of this well studied system following pharmacologically relevant perturbations. The authors use the model as an effective example of the use of Systems Biology to aid understanding of drug action. Bibliographic References
