Conjugation glucuronyl transferases

The functional form of thyroxine (T3) is generated by the deiodination of T4, and PCBs can influence the tissue levels of this form by disturbing metabolism, as well as by reducing the binding of T4. PCBs have been shown to inhibit the sulfation of thyroid hormones and the deiodination of T4 to T3. They can also induce the glucuronyl transferase that conjugates T4 (Brouwer et al. 1998). 

Glucuronyl transferases A group of enzymes that catalyze the formation of conjugates between glucuronide and a xenobiotic (usually a phase I metabolite). 

The assessment of clearance is complicated by the numerous mechanisms by which compounds may be cleared from the body. These mechanisms include oxidative metabolism, most commonly by CYP enzymes, but also in some cases by other enzymes including but not limited to monoamine oxidases (MAO), flavin-containing monooxygenases (FMO), and aldehyde oxidase [45, 46], Non-oxidative metabolism such as conjugation or hydrolysis may be effected by enzymes such as glucuronyl transferases (UGT), glutathione transferases (GST), amidases, esterases, or ketone reductases, as well as other enzymes [47, 48], In addition to metabolic pathways, parent compound may be excreted directly via passive or active transport processes, most commonly into the urine or bile. 

The metabolites of ondansetron have been examined in urine and bile from rat and dog. The major pathways for metabolism of ondansetron are A-demethylation and hydroxylation Scheme 7.7). However, whereas A-de-methylation predominates in dog, this is only a minor metabolic route in rat. Hydroxylation may occur at the 6, 7 or 8 position in the carbazolone ring. Hydroxy metabolites of ondansetron are excreted predominantly as glucuronide or sulphate conjugates. Studies with immobilised glucuronyl-transferase (Heath, S.E., personal communication) have demonstrated that O- and A-glucuronidation of ondansetron metabolites may occur. 

One of the most important phase II conjugation reactions is that catalyzed by the glucuronyl transferases. A number of functional groups have the potential to be glu-curonidated as shown in Table 7.3, but phenol and carboxylic acid functions are of prime importance to the medicinal chemist. 

S8) to be located in the microsome fraction of the liver. The neonatal development of this conjugating system has been studied by Brown et al. (B17) in the guinea pig. They were unable to detect the presence of bilirubin glucuronyl transferase in liver microsomes from fetal and newborn animals and, using o-aminophenol as a glucuronyl acceptor, were... 

Phase II conjugation represents enzyme reactions that lead to the addition of a highly water soluble molecule to the chemical that is being metabolized, leading to highly water soluble "conjugates" to allow efficient excretion. Examples of Phase II enzymes are UDP-glucuronyl transferase (UGT), sulfotransferase (ST),... 

Glucuronyl transferases are membrane-bound enzymes primarily associated with the endoplasmic reticulum of liver cells. Glucuronidation takes place to a lesser extent in cells of many other tissues as well. Sulfate conjugation represents the important metabolic alternative to glucuronidation being mediated by a soluble enzyme system (2). Glucuronidation is favored for lipophilic compounds while the lower molecular weight, hydrophilic xenobiotics in the cytosol are preferred substrates for sulfation. 

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