The Influence of Bilirubin on Oxidative Phosphorylation and Related Reactions in Brain and Liver Mitochondria: Effects of Protein‐binding

Abstract

SUMMARY 1. The uncoupling of oxidative phosphorylation of liver mitochondria by bilirubin does not occur in the presence of equimolar quantities of human serum albumin. With brain mitochondria, however, albumin was not protective. 2. A similar protective effect of albumin for liver, but not for brain, mitochondria was observed in studies of the effects of bilirubin on the 32Pi‐ATP exchange reaction. 3. The latent ATPase of fresh brain mitochondria is activated by Mg2+ but only slightly by DNP. Bilirubin increased the Mg2+ stimulated ATPase activity in liver mitochondria but depressed this activity in brain mitochondria. These effects were uninfluenced by protein binding. 4. Isotope studies with [14C]bilirubin demonstrated that the affinity of brain mitochondria for albumin‐bound bilirubin is not greater than that of liver mitochondria. 5. The greater toxicity of protein‐bound bilirubin for brain mitochondria than for liver mitochondria might be related to the greater lipid content of brain mitochondria.

Apoptosis in Murine Hepatoma Hepa 1c1c7 Wild-Type, C12, and C4 Cells Mediated by Bilirubin

“…The involvement of the mitochondrial-dependent pathway is consistent with recent reports indicating that bilirubin interferes with membrane permeabilization in isolated mitochondria from rat brain and liver tissues (Rodrigues et al, 2000). Not surprisingly, mitochondria were found to be involved in the apoptotic response, because they are target sites for bilirubin toxicity (Menken et al, 1966) and removal by enzymatic oxidation, at least in brain (Hansen and Allen, 1997). The magnitude of the cytochrome c response reflects the differences observed in cell viability between WT, C12, and C4 cells incubated with bilirubin, implying a role for the AHR in WT cells.…”

Sodium arsenite induced alterations in bilirubin excretion and heme metabolism

“…These results suggest that the effect of arsenic on the content of cytochrome P-450 may be a consequence of two different mechanisms: a direct interaction between AsIII and the regulatory site of heme oxygenase, inducing its activity and decreasing both the "free" heme pool and the cytochrome P-450 content (5), and/or a direct binding of AsIII to a specific -SH cysteinyl residue of the apo-cytochrome P-450 (32), inhibiting its assembly to heme, which after increasing the "free" heme pool, is converted to bilirubin. In addition, the morphological and biochemical hepatic damage caused by bilirubin (33)(34)(35) appears to be consistent with that observed in animals during subchronic AsIII treatment (36). Therefore, bilirubin may be a contributing factor in the hepatotoxicity of arsenic.…”

“…In addition, the morphological and biochemical hepatic damage caused by bilirubin (33)(34)(35) appears to be consistent with that observed in animals during subchronic AsIII treatment (36). Therefore, bilirubin may be a contributing factor in the hepatotoxicity of arsenic.…”

Experimental Bilirubin Encephalopathy: Importance of Total Bilirubin, Protein Binding, and Blood-Brain Barrier

“…There is, on the other hand, abundant in vitro evidence that albumin-bound bilirubin is not toxic (11)(12)(13)(14)(15) and that the concentration of free bilirubin acid may be responsible for cell injury (4,16). Recently, we examined the possibility that yellow staining may not be harmful if it represents the transport of albumin bound bilirubin across a disrupted BBB.…”