The Mechanism of Bilirubin Toxicity Studied with Purified Respiratory Enzyme and Tissue Culture Systems^*

Role of hyperbilirubinemia in the impairment of osteoblast proliferation associated with cholestatic jaundice.

“…Our finding that unconjugated bilirubin inhibits the proliferation of normal hOB cells is consistent with results in other types of cells in which inhibition or toxic effects have been observed (24)(25)(26)(27)(28)(29)(30). However, in the dose-response experiment, we found no evidence of increased cell death as assessed by failure to exclude trypan blue at higher concentrations of bilirubin.…”

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

“…This effect appears to be specific to the unconjugated form of bilirubin as the metabolic precursor, biliverdin, and the stable conjugate, BDT, did not alter cell viability. These observations are consistent with the findings of Cowger et al, 65 who showed that 25 M bilirubin, but not biliverdin, blocks cellular ATP generation by L-929 murine fibroblasts. As colon cancer cells express message for biliverdin reductase, the absence of a cytotoxic effect of biliverdin suggests that cellular biliverdin reductase activity is insufficient to produce enough bilirubin to induce apoptosis.…”

“…60 Since the original observation by Day in 1954 that bilirubin inhibits the respiratory activity of rat brain homogenate, 71 a number of studies have examined the effect of bilirubin on mitochondrial function. At the cellular level, Cowger et al 65 demonstrated that bilirubin, when added to the culture medium at concentrations ranging from 5-250 M (in the absence of albumin), uncouples oxidative phosphorylation in L-929 cells with a potency over 16 times greater than biliverdin. Similarly, Chuniaud et al 24 showed that mitochondrial activity, as assessed by MTT metabolism, in cultured rat brain astrocytes and human fibroblasts is impaired by bilirubin and that this effect occurs at bilirubin:human serum albumin ratios ranging 0.5-1.5.…”

Bilirubin: An Endogenous Product of Heme Degradation with Both Cytotoxic and Cytoprotective Properties

“…Early studies established that mitochondria might be a major target for UCB neurotoxicity, as demonstrated by impairment in mitochondrial function leading to the uncoupling of oxidative phosphorylation (Zetterstrom and Ernster, 1956;Cowger et al, 1965;Diamond and Schmid, 1967;Menken and Weinbach, 1967;Mustafa et al, 1969). Additional effects of UCB in neural tissues and neuronal cell lines include inhibition of DNA and protein synthesis, changes in carbohydrate metabolism, and modulation of neurotransmitter synthesis and release.…”