Glutathione-bilirubin conjugates

Fig. 11. Formation of bilirubin-glutathione conjugates. This mechanism for conjugation of bilirubin and GSH was proposed by Odell et al. (01).

MRP2 (ABCC2) LTC4, bilirubin-glucuronide, estradiol 17 3-glucuronide, dianionic bile salts, anionic conjugates, glutathione disulfide, and others... 

Once bilirubin enters the hepatocytes, it can bind to certain cytosolic proteins, which help to keep it solubilized prior to conjugation. Ligandin (a family of glutathione S-transferases) and protein Y are the involved proteins. They may also help to prevent efflux of bilirubin back into the blood stream. 

Figure 32-15. Diagrammatic representation of the three major processes (uptake, conjugation, and secretion) involved in the transfer of bilirubin from blood to bile. Certain proteins of hepatocytes, such as ligandin (a family of glutathione S-transferase) and Y protein, bind intracellular bilirubin and may prevent its efflux into the blood stream. The process affected in a number of conditions causing jaundice is also shown.

Figure 22-3. Transport and hepatic metabolism of bilirubin. Bilirubin that is produced in phagocytes is transported to liver as an albumin-bilirubin complex. Uptake into the hepatocytes takes place in liver sinusoids. Within the hepatocyte, bilirubin is transported to the endoplasmic reticulum (microsomes) bound to glutathione S-transferase (GST). Bilirubin is made water soluble by addition of one or two glucuronic acid moieties obtained from UPD-glucuronic acid, catalyzed by bilirubin-UDP-glucuronyltransferase. The product, conjugated bilirubin, is transported across the bile canalicular membrane for secretion into the biliary system, with subsequent movement into the intestines.

Bunamiodyl (B19, S26) and iodopanoic acid (S17) cause an elevation of BSP retention. These compounds, and the related iodinated aryl compound iodipamide, competitively inhibit the enzyme S-aryl glutathione transferase (B38). However, these compounds also affect the excretion of bilirubin (B21, B33), which is excreted as a glucuronide, of indocyanine green (H4), which is not conjugated by the liver, and of conjugated bilirubin (B21). Bunamiodyl and iodipamide reduce the uptake of BSP by liver slices (B6, B7) and by the isolated perfused liver (B19). 

Ibufenac reduces hepatic clearance of both indocyanine green and bilirubin (H5). This drug also inhibits glucuronyl transferase (H5) and S-aryl glutathione transferase (B38). In vivo, phenylbutazone depresses bilirubin excretion, but not that of BSP in vitro, the enzymes conjugating bilirubin and BSP, respectively, are both inhibited. There is no effect on the clearance of indocyanine green (H5). 

This anticoagulant drug causes inhibition of bilirubin clearance and conjugation (H5) as well as inhibition of S-aryl glutathione transferase (B38). The action of this drug on dye excretion has not been reported. 

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