|Topic:||Clinical Significance of Glucuronate .|
In the adult human, a significant number of erythrocytes die each day. This turnover releases significant amounts of the iron-free portion of heme, porphyrin, which is subsequently degraded. The primary sites of porphyrin degradation are found in the reticuloendothelial cells of the liver, spleen and bone marrow. The breakdown of porphyrin yields bilirubin, a product that is non-polar and therefore, insoluble. In the liver, to which is transported in the plasma bound to albumin, bilirubin is solubilized by conjugation to glucuronate. The soluble conjugated bilirubin diglucuronide is then secreted into the bile. An inability to conjugate bilirubin, for instance in hepatic disease or when the level of bilirubin production exceeds the capacity of the liver, is a contributory cause of jaundice.
The conjugation of glucuronate to certain non-polar drugs is important for their solubilization in the liver. There are numerous genes in the human genome that encode UDP-glucuronyltransferases which themselves belong to the large superfamily of glycosyltransferases. There are four UDP-glucuronyltransferase families in humans identified as the UGT1, UGT2, UGT3, and UGT8 families.There are nine functional enzymes of the UGT1 family that are derived through the splicing of nine alternative first exons to the four common exons (2, 3, 4, and 5). These enzymes are designated UGT1A1–UGT1A9 (described in more detail in the Heme Metabolism page). The UGT2 gene family is composed of three UGT2A members (UGT2A1, UGT2A2, and UGT2A3) and seven UGT2B members (UGT2B,4, UGT2B7, UGT2B10, UGT2B11, UGT2B15, UGT2B17, and UGT2B28). The UGT3 family is composed of two members (UGT3A1 and UGT3A2) and the UGT8 family is composed of a single member (UGT8A1). Although the preferred substrate for these enzymes is UDP-glucuronate as the glycosyl donor, other UDP sugars (e.g. UDP-glucose and UDP-xylulose) may be used. Whereas most all of these enzymes catalyze reactions designed to detoxify both endogenous and exogenous compounds, the UGT8A1 enzyme (identified as UDP-galactose ceramide galactosyltransferase and abbreviated CGT) carries out a biosynthetic reaction in galactocerebroside synthesis.
Glucuronate-conjugated drugs are more easily cleared from the blood by the kidneys for excretion in the urine. The glucuronate-drug conjugation system can, however, lead to drug resistance; chronic exposure to certain drugs, such as barbiturates and AZT, leads to an increase in the synthesis of the UDP-glucuronyltransferases in the liver that are involved in glucuronate-drug conjugation. The increased levels of these hepatic enzymes result in a higher rate of drug clearance leading to a reduction in the effective dose of glucuronate-cleared drugs.
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