Glucuronide formation

This is a major, type 1, conjugation reaction occurring in most species with a wide variety of substrates, including endogenous substances. It involves the transfer of glucuronic acid in an activated form as uridine diphosphate glucuronic acid (UDPGA) to hydroxyl, carboxyl, nitrogen sulphur and occasionally carbon atoms. The UDPGA is formed in the cytosol from glucose-1-phosphate in a two-step reaction (figure 4.48). The first step, addition of the UDP, is catalysed by UDP glucose pyrophosphorylase, the second step by UDP glucose dehydrogenase.

The enzyme catalysing the conjugation reaction, UDP-glucuronosyl transferase (glucuronyl transferase), exists in possibly four or more forms, each with different substrate specificities. The following are examples of substrates for the different forms although some substrates may be glucuronidated by more than one form of the enzyme: form A 1-napthol; form B bilirubin; form C oestrone, form D morphine. The enzymes are located in the endoplasmic reticulum and are found in many tissues including the liver.

Conjugation with glucuronic acid involves nucleophilic attack by the oxygen, sulphur or nitrogen atom at the C-1 carbon atom of the glucuronic acid moiety. Glucuronides

FIGURE 4.48 Formation of uridine diphosphate glucuronic acid (UDPGA).
Liver Glucuronidation Image
FIGURE 4.49 Formation of ether and ester glucuronides ofphenol and benzoic acid respectively.
Glucuronidation
FIGURE 4.50 Glucuronidation of aniline and N-hydroxyacetanilide.

are therefore generally b in configuration. Conjugation with hydroxyl groups gives ether glucuronides and with carboxylic acids, ester glucuronides (figure 4.49). Amino groups may be conjugated directly, as in the case of aniline (figure 4.50) or through an oxygen atom as in the case of ^-hydroxy compounds, such as the carcinogen A-hydroxyacetylaminofluorene (figure 4.51). Certain thiols may be conjugated directly through the sulphur atom (figure 4.52). Glucuronic acid conjugated directly to carbon atoms has been reported such as with the drug phenylbutazone. Although conjugation generally decreases biological activity, including toxicity, occasionally the latter is increased, as in the case of acetylamino-fluorene. The A^hydroxy-

Formation Ethyl Glucuronide
FIGURE 4.51 Formation of N-hydroxyacetylaminofluorene glucuronide.
FIGURE 4.52 Formation of 2-mercaptobenzothiazole-S-glucuronide.
Formation Ethyl Glucuronide
FIGURE 4.53 Formation of ethereal sulphates ofphenol and ethyl alcohol.

glucuronide is a more potent carcinogen (figure 4.51).

Glucose conjugates (glucosides) may sometimes be formed, especially in insects, and the mechanism is analogous to that involved in the formation of glucuronides. Xylose and ribose are also sometimes utilized, for example, 2-hydroxynicotinic acid has been shown to form an ^-ribose conjugate. Analogues of purines and pyrimidines may be conjugated with ribose or ribose phosphates to give ribonucleotides and ribonucleosides.

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