UGT enzymes

Dehal, S.S., Gagne, P.V., Crespi, C.L. and Parren, C.J. (2002) Effect of common organic solvent on human UGT enzyme activities. 11th North American ISSX Meeting, October 27-31, 2002, Orlando, Florida, USA, Abstract 370. 

In silico methods able to highlight the most likely position(s) for conjugation may facilitate the development of new molecular scaffold with decreased U GT sensitivity, thus making the compounds more resistant to UGT conjugation. This may be another route for the development of more effective compounds, made possible by additional structural information on UGT enzymes available (Figure 12.2). 

Although UGTs catalyze only glucuronic acid conjugation, CYPs catalyze a variety of oxidative reactions. Oxidative biotransformations include aromatic and side chain hydroxylation, N-, O-, S-dealkylation, N-oxidation, sulfoxidation, N-hydroxylation, deamination, dehalogenation and desulfation. The majority of these reactions require the formation of radical species this is usually the rate-determining step for the reactivity process [28]. Hence, reactivity contributions are computed for CYPs, but a different computation is performed with the UGT enzyme (as described in Section 12.4.2). 

Nicotine glucmonidation results in an N-quatemary glucmonide in humans (Benowitz et al. 1994). This reaction is catalyzed by uridine diphosphate-glucuronosyltransferase (UGT) enzyme(s) producing (5)-nicotine-N-P-glucmonide. About 3-5% of nicotine is converted to nicotine glucuronide and excreted in urine in humans. 

Figure 14.5 Intestinal resveratrol metabolic pathway proposed after oral administration using Caco-2 monolayers. SULT and UGT enzymes shown in bold represent the predominant contribution to sulfate and glucuronide formation.

Induction of the individual UGT enzymes resulting in increased clearance... 

Major interactions involving individual UGT enzymes will be discussed in detail along with a brief discussion of the function of each enzyme. A table of substrates, inducers, and inhibitors for the UGT enzymes is provided in the appendix to this chapter. 

Table 11 Tissue Distribution and Specific Substrates for Human UDP-Glucuronosyl-transferase (UGT) Enzymes...

Typical reactions catalyzed by UGT enzymes require the cofactor uridine diphosphate-glucuronic acid, UDPGA. However, the C-terminus of all UGT enzymes contains a membrane-spanning domain that anchors the enzyme in the endoplasmic reticulum, and the enzyme faces the lumen of the endoplasmic reticulum, where it is ideally placed to conjugate lipophilic xenobiotics and their metabolites generated by oxidation, reduction, or hydrolysis. The lumenal... 

Glucuronidation is an important detoxification pathway in humans. Many therapeutic drugs and their metabolites are substrates for UDP-glucuronyltransferase (UGT), leading to the formation of usually inactive glucuronides, which are then excreted via bile or urine. Individual UGT enzymes are defined in a similar way to the GYP enzymes by family (1 or 2), subfamily (A or B) and an Arabic numeral representing the... 

CORTICOSTEROIDS MYCOPHENOLATE 1 plasma concentrations of mycophenolate and risk of transplant rejection Corticosteroids induce UGT enzymes and multidrug resistance-associated protein 2, involved in disposition of mycophenolate Intervention to prevent rejection is mandatory, t mycophenolate dosage to maintain therapeutic blood levels. As important is to monitor levels following steroid withdrawal to prevent adverse outcomes... 

Activity in Liver Tissue The liver contains the highest content of UGT enzymes, and most if not all of the 16 functional UGT genes are expressed.56 The activities of the enzymes expressed in intestine and liver seem to be very similar. 

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