Bilirubin, a curse and a boon.

B oth hydrophobic bile salts 2 and unconjugated bilirubin (UCB) induce apoptosis in cultured cells at moderately elevated concentrations and cell necrosis at higher concentrations. Retention of bile salts in cholestasis is believed to cause secondary damage to hepatocytes, and retention of UCB in severe neonatal jaundice is known to cause bilirubin encephalopathy. For both agents, the cytotoxicity results from damage to mitochondrial membranes, with collapse of the transmembrane potential and generation of a mitochondrial membrane permeability transition, 2 6 and ursodeoxycholic acid or its amidates can prevent apoptosis by inhibiting this process. 2 7 It is therefore surprising that, as reported by Granato et al in this issue of Gut, UCB, at concentrations far above those known to be cytotoxic to neurones and astrocytes, is protective against apoptosis induced in cultured rat hepatocytes by the hydrophobic bile salt glycochenodeoxycholate (GCDC) [see page 1774]. This finding raises interesting questions concerning whether UCB is a curse or a boon, and why various organs and tissues have such different susceptibilities to toxicity from these substances.