Glucuronate/glucuronic acid bilirubin conjugation with

Conjugation of Bilirubin With Glucuronic Acid Occurs in the Liver... 

Figure 32-14. Conjugation of bilirubin with glucuronic acid. The glucuronate donor, UDP-glucuronic acid, is formed from UDP-glucose as depicted. The UDP-glucuronosyl-transferase is also called bilirubin-UGT.

In the hver, bilirubin is made water-soluble by conjugation with two molecules of glucuronic acid and is secreted into the bile. The action of bacterial enzymes in the gut produces urobihnogen and urobihn, which are excreted in the feces and urine. 

Bilirubin is the waste product derived from haem catabolism. In order to be eliminated from the body, mainly via the gut, bilirubin must be processed through the liver (see Section 6.4). Bilirubin is, however, insoluble in water, so to reach the liver from the spleen where a substantial amount of red cell destruction occurs, bilirubin must first be bound to albumin. As blood perfuses the liver, bilirubin is transported into the hepatocyte where it is conjugated with glucuronic acid prior to excretion. 

With washed microsomal preparations from the liver of guinea pig, rat, rabbit, mouse, and cat, conjugation of bilirubin also occurred at appreciable rates in the absence of added bivalent cation (P3). With digitonin-activated preparations from rat liver, glycosyl transfer rates were, respectively, 16-33%, 0-38%, and 58-78% of the values found at nearsaturation of Mg + when UDP-glucuronic acid, UDP-xylose, or UDP-glucose were assayed (F3, HIO). The great variability of the rates could point to an artifact. 

In the procedure of Wong (W12) bilirubin is incubated enzymatically with [U- C]UDP-glucuronic acid of known specific activity. The derived azo pigments are transferred quantitatively to a thin-layer plate and are separated. The spot of conjugated azo pigment is eluted and counted. With other radioactive UDP-sugars, extension of the procedure to the corresponding transfer processes is obvious. 

Fig. 3. A possible mechanism for the conjugation of bilirubin with glucuronic acid (BIO).

Bilirubin is a lipid-soluble substance and for it to give a direct van den Bergh reaction it must be converted into a water-soluble state. This can be achieved in alkaline solution or by the use of solvents, such as ethanol, which are soluble in both water and chloroform (Cl). Conjugation with glucuronic acid also causes the solubilization of bilirubin and in view of the well-known versatility of the liver s detoxifying systems, the possibility that bilirubin may be conjugated with other substances has been considered. 

Figure 22-1. Production of bilirubin (BR). The degradation of I e l 3-hcme by molecular oxygen and NAD PH, catalyzed by microsomal heme oxygenase, produces biUverdin, CO, and Fe+2. Subsequent reduction of biliverdin by NADPH, catalyzed by biliverdin reductase, produces bilirubin. Bilirubin that is produced in phagocytes from degradation of senescent erythrocytes is transported to liver for conjugation with glucuronic acid, catalyzed by bilirubin-UDP-glucuronyltransferase. In some cells, the bilirubin is used as an antioxidant, where it recycles through the biliverdin reductase reaction.

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.

Since mutism with olanzapine has been reported in cases of overdose, and detoxification of bilirubin by conjugation with glucuronic acid, the pathway olanzapine uses, is altered in Gilbert s syndrome, which affects 10% of the population, the authors claimed that we should keep in mind idiopathic unconjugated hyperbilirubinemia when prescribing olanzapine. 

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