Glucuronyl-transferase

Pargyline hydrochloride (Eutonyl, (V-methyl-n-propargylbenzylamine hydrochloride) [306-07-0] M 195.7, m 154-155 , 155 , pK 6.9. Recrystd from EtOH-Et20 and dried in vacuo. It is very soluble in H2O, in which it is unstable. The free base has b 101-103°/ 1mm. It is a glucuronyl transferase inducer and a monoamine oxidase inhibitor, [von Braun et al. Justus Liebigs Ann Chem 445 205 1928, Yeh and Mitchell Experientia 28 298 1972 Langslrom et al. Science 225 1480 1984.]... 

UDP-Glucuronyl Transferase Ultrarapid Metabolizer Unstable Angina Unwanted Effects UPR... 

VDP-Glucuronyl transferases (henceforward simply glucuronyl transferases) exist in a number of different forms with contrasting, yet overlapping, substrate... 

The microsomal fraction consists mainly of vesicles (microsomes) derived from the endoplasmic reticulum (smooth and rough). It contains cytochrome P450 and NADPH/cytochrome P450 reductase (collectively the microsomal monooxygenase system), carboxylesterases, A-esterases, epoxide hydrolases, glucuronyl transferases, and other enzymes that metabolize xenobiotics. The 105,000 g supernatant contains soluble enzymes such as glutathione-5-trans-ferases, sulfotransferases, and certain esterases. The 11,000 g supernatant contains all of the types of enzyme listed earlier. 

Apart from monooxygenases, other enzymes concerned wih xenobiotic metabolism may also be induced. Some examples are given in Table 2.5. Induction of glucuronyl transferases is a common response and is associated with phenobarbital-type induction of CYP family 2. Glutathione transferase induction is also associated with this. A variety of compounds, including epoxides such as stilbene oxide and... 

Emphasis is given to the critical role of metabolism, both detoxication and activation, in determining toxicity. The principal enzymes involved are described, including monooxygenases, esterases, epoxide hydrolases, glutathione-5 -transferases, and glucuronyl transferases. Attention is given to the influence of enzyme induction and enzyme inhibition on toxicity. 

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). 

Morcillo, Y., Janer, G., and O Hara, S.C.M. et al. (2004). Interaction of tributyl tin with cytochrome P450 and UDP glucuronyl transferase systems of fish in vitro smdies. Environmental Toxicology and Chemistry 23, 990-996. 

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. 

Zidovudine (AZT, ZDV) Retrovi r 1 00-mg caps, 300-mg tabs, 1 0 mg/mF intravenous solution, 1 0 mg/mF oral solution 300 mg bid 1 00 mg tid in severe renal impairment or HD None Bone marrow suppression macrocytic anemia or neutropenia gastrointestinal intolerance, headache, insomnia, asthenia Glucuronyl transferase and renal... 

Stevenson, D.E. and Hubl, U. (1999) Optimization of /3-D-glucuronide synthesis using UDP-glucuronyl transferase Enzyme and Microbial Technology 24, 388-396. 

Easterbrook, J., Liu, C., Sakai, Y. and Li, A.P. (2001) Effects of organic solvents on the activities of cytochrome P450 isoforms, UDP-dependent glucuronyl transferase, and phenol sulfotransferase in human hepatocytes. Drug Metabolism and Disposition The Biological Fate of Chemicals, 29, 141-144. 

Scheme 7. General glucuronidation reaction catalyzed by UDP-glucuronyl transferases.

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. 

For exogenous compounds such as drugs, various enzymes involved in both phase I and phase II metabolic routes are present, e.g. various isoforms of cytochrome p450, cytochrome b5, glucuronyl transferase and sulfotransferase [15]. 

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. 

Glucuronidation involves the transfer of D-glucuronic acid from UDP-a-glu-curonic acid to an acceptor compound. The family of enzymes which catalyze this reaction are the UDP-glucuronyl transferases [16]. The reaction proceeds by nucleophilic Sn2 substitution of the C-1 carbon of glucuronic acid, the product undergoing inversion of configuration. The mechanism is illustrated schematically in Figure 7.21. 

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