Fig. 1From: Integrative and theoretical research on the architecture of a biological system and its disorderEffect of sunitinib on metabolic pathways were simulated by sequential simulation of previously reported models. a–e The simulation result suggests that sunitinib treatment induces oxidative stress. Phosphorylase kinase (PHK) gamma-related pathways were integrated and simulated using three divided models (a) (for expanded version, see Electronic Supplementary Material figure). The pathways highlighted by black-boxed regions in a are enlarged in b–e, which also display the simulated change in the amount of different molecules as a function of free sunitinib concentration. f, g The prediction was confirmed in in vivo experiments using a mouse model. A decrease in the glutathione/oxidized glutathione (GSH/GSSG) ratio was observed in many organs of mice treated with sunitinib. In addition, elimination of oxidative stress by α-tocopherol nicotinate (α-T.N.) can prevent organ toxicities. ALT Alanine aminotransferase, GPx glutathione peroxidase, GR glutathione reductase. The results of liver toxicity analyses are shown as representative dataBack to article page