Glucuronyl metabolites

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

Primary Arylamines, and N-Methyl Arylamines. Putative ultimate carcinogenic metabolites are designated I-XIII. Ac, acetyl Gl, glucuronyl. 

Potentially, individuals with low activities of the enzymes phenol sulfotransferase and glucuronyl-transferase may be more susceptible to phenol toxicity. Persons with ulcerative colitis may have an impaired capacity to sulfate phenol (Ramakrishna et al. 1991), which may increase the amount of unchanged phenol that is absorbed following oral exposure. Neonates may also be more susceptible to toxicity from dermally-applied phenol because of increased skin permeability and proportionately greater surface area. A study in which 10-day-old rats were more sensitive to lethality following oral exposure to phenol than 5-week-old or adult rats (Deichmann and Witherup 1944) further suggests that the young may be more sensitive to phenol. (For a more detailed discussion please see Section 2.6.) Because phenol is a vesicant, individuals with sensitive skin or pulmonary incapacity may be more sensitive to phenol. Individuals with kidney or liver diseases that impair metabolism or excretion of phenol and phenol metabolites may be more susceptible to phenol. 

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. 

Mycophenolate mofetil is rapidly absorbed after oral administration, and the bioavailability of its oral dose is 94%. It is metabolized by esterases to free MPA, which is the active metabolite. The enterohepatic recirculation plays a crucial role in the serum levels of MPA. The active metabolite is further metabolized by glucuronyl transferase and is eliminated (90%) in urine as the MPA glucuronide (MPAG) as a result of the organic anion transport system in the proximal tubule. A small amount is excreted in feces. 

Acetaminophen is metabolized mainly by liver glucuronyl transferase to form the inactive conjugate. A minor pathway (via P450) results in formation of a reactive metabolite (N-acetylbenzoquinoneimine) that is inactivated by glutathione (GSH). In overdose situations, the finite stores of GSH are depleted. Once this happens, the metabolite reacts with hepatocytes, causing nausea and vomiting, abdominal pain, and ultimately liver failure due to centrilobular necrosis. Chronic use of ethanol enhances liver toxicity via induction of P450. 

The most important mammalian conjugation molecules for pollutants and their metabolites are uronic acids, glutathione, amino acids, taurine, and sulphate. The conjugation is catalyzed by liver enzymes like UDP-glucuronyl-transferases, sulfotransferases, glutathione S-transferases and amino acid N-acyltransferases. 

The most important adverse effect of abacavir is a unique and potentially fatal hypersensitivity syndrome. This syndrome is characterized by fever, abdominal pain, and other gastrointestinal complaints a mild maculopapular rash and malaise or fatigue. Respiratory complaints (cough, pharyngitis, dyspnea), musculoskeletal complaints, headache, and paresthesias are reported less commonly. Abacavir is rapidly absorbed and is metabolized to inactivate metabolites by alcohol dehydrogenase and glucuronyl transferase. Alcohol decreases the elimination of abacavir and prolongs its half-life. 

Chloramphenicol is completely absorbed from the gastrointestinal tract and is distributed widely throughout the body, including the cerebrospinal fluid. It is metabolized in the liver by glucuronyl transferase, and the metabolites are excreted by the kidneys. Newborn infants cannot metabolize chloramphenicol readily. 

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