Negundoside, an iridiod glycoside from leaves of Vitex negundo, protects human liver cells against calcium-mediated toxicity induced by carbon tetrachloride

Figure 18 Proposed sequence of events and mechanism involved in the toxicity of CCl₄ and cytoprotection offered by NG. CCl₄ is activated by CYP 450 2E1 system and converted into trimethyl CCl₃ radicals inducing oxidative stress (increased ROS inducing membrane lipid peroxidation) and disturbed cellular Ca²⁺ homeostasis. Increase in intracellular Ca²⁺ concentrations leads to activation of phospholipase A2 and a decline in cAMP levels. All these signaling events converge onto the mitochondrial-initiating mitochondrial pore transition and ultimately to cellular injury. The highly increased levels of ROS is, in part, the consequence of the increase in Ca²⁺, and also as a result of mitochondrial permeabilization resulting in activation of Ca²⁺ dependent proteases. NG exerts a protective effect via inhibition of oxidative stress, maintenance of disrupted intracellular calcium homeostasis and inactivation of Ca²⁺-dependent proteases.