Pathobiochemical mechanisms of hepatocellular damage following lipid peroxidation

In hepatocytes, cytotoxic events induced by haloalkanes or acute iron-overload exhibit neither a quantitative nor a temporal correlation to lipid peroxidation or covalent binding. Thus, secondary pathological mechanisms have been postulated linking initial focal reactions of free radicals and end stage pathological consequences. Due to the crucial role of plasma-membrane integrity in the cytotoxic process it has to be supposed that relevant secondary pathological mechanisms finally impair the physico-chemical and functional properties of this membrane. Based on recent developments a chain of causality is proposed as a two-step activation of phospholipase A2 producing cytolytic amounts of lysophosphatides. In this cascade, the initial activating step is a decrease of membrane lipid fluidity induced by lipid peroxidation and/or by calcium binding and intramembranous formation of 4-hydroxynonenal. This enzyme activation is further amplified by the early rise of cytosolic calcium. Consequently, increasing amounts of lysophosphatides progressively impair membrane configuration thus improving the substrate accessibility for phospholipase A2 in a second activation step. Finally, the lysophosphatides reach plasma membrane-lytic concentrations by this autocatalytic enzyme activation.