2.7.2. Phase II: Glucuronidation

2.7.2. Phase II: Glucuronidation

UGTs carry out Phase II metabolism by catalyzing glucuronidation (formation of a linkage between glucuronic acid and a nucleophile), which leads to easier elimination of xenobiotics. Some compounds are metabolized by UGTs directly, but the physiological site of attack is often a hydroxy or amino group unmasked (or, in the case of hydroxyl, introduced) by Phase I metabolism. Though the enzymes are distributed throughout the human body, most glucuronidation in humans takes place in the liver. Some, however, - e.g., that due to UGTs 1A8 and 1A10 - occurs in the GI tract.

We collected data from about 270 publicly-available literature sources (e.g., Lewinsky 2005; Sorich 2006) and have developed classification ANNEs for nine UGT isoforms that are responsible for much of Phase II drug metabolism: UGTs 1A1, 1A3, 1A4, 1A6, 1A8, 1A9, 1A10, 2B7 and 2B15. The number of compounds used to train these nine models ranged from 196 to 319.

Independent test sets were used for validation of all models. Performances of individual models are given in the table below. The models return a binary “Yes/No” classification provided the molecule in question contains some suitably nucleophilic group. If no such group is present, a classification of “NoSites” is returned.

Each substrate classification model has an associated characteristic hierarchy of glucuronidation site specifications that can be used to identify the glucuronide most likely to be produced by that isoform.