Some membrane effects of bilirubin

Abstract

The respiratory lesions induced by bilrirubin do not seem to adequately explain the great toxicity of this bile pigment. Bilirubin is highly lipophilic; thus, it was postulated that bilirubin has a general effect on membrane systems. Experimental evidence to support this hypothesis comes from studies using modified L-929 tissue culture cells, rat liver, bovine heart, and brain of several species. At a bilirubin concentration of 25 μM the plasma membrance of L-929 cells following a lag phase of 60–90 minutes becomes permeable to large dye molecules concurrent with the extrusion of protein molecules. Earlier changes in the plasma membrane can be shown by alterations in Na+ and K+ transport occurring within the first hour of exposure to bilirubin.Mitochondrial membranes are exquisitely sensitive to bilirubin. Low (<20 μM) concentrations increase and high (>50 μM) concentrations decrease the respiration of liver and heart mitochondria, but brain respiration is always inhibited without this biphasic effect. Bilirubin in micromolar concentrations abolishes respiratory control, uncouples oxidative phosphorylation, and induces high amplitude irreversible swelling (Km is 2.5 μM for swelling in liver and heart. (Brain is slightly more sensitive (Km is 2 μM). All of these mitchondrial reactions are membrane linked. Electron microscopy confirms the biochemical data of swelling.Lysosomes of rat liver and L-929 cells demonstrate increased permeability within one hour of exposure to bilirubin using acid phosphatase activity as a monitor of membrane fragility. This effect is seen at relatively high bilirubin levels (500 μM) but preliminary evidence suggests concentration of bilirubin by lysosomes.