drugs, behind P450s and UGTs (Fig. 2.1a). These enzymes are collectively
found in many places, including the liver and plasma.
One group of esterases has ana,b-fold and is prominent in the liver cytosol
(Quinn, 1997). Acetylcholinesterase, butyl cholinesterase, and lipases have been
used as models for these esterases. Generally esterases also have amidase
activity (andvice versa, due to the basic mechanisms). All esterases appear to
use a catalytic triad to activate a nucleophile, which is used to form an enzyme-
acyl intermediate. The triad consists of a nucleophile, a general base catalyst,
and an acidic residue.
Some esterases are loosely bound to the endoplasmic reticulum and
constitute a separate family, using ester and amide substrates. At least six of
these have been reported in humans (Sone and Wang, 1997). Some evidence
exists for induction and other regulation of this group. In general, the soluble
esterases do not seem to be inducible.
Not every ester cleavage is due to esterases. For instance a P450 can catalyze
an oxidative ester cleavage via carbon hydroxylation (Guengerich, 1987).
Esterases reactions are prominent in the metabolism of drugs and pesticides.
The inhibitors of esterases are generally strong electrophiles, some of which are
intermediates generated during the metabolism of pesticides (e.g., the inhi-
bition of acetylcholinesterase is a classic case in this area (Quinn, 1997)).
2.8 Summary
The purpose of this section has been an overview of the major enzymes
systems. Although this group of reactions has often historically been treated
together as Phase I metabolism, the group is very heterogeneous in many
respects and individual reactions have been treated separately. Knowledge of
these systems has been fundamental in influencing how drug development is
conducted. However, it should still be emphasized that predictions are difficult
in this area, based only on drug structures, and that experiments remain a
necessary part of the process, in terms of establishing pathways and enzymes
involved.
References
Al-Waiz M, Ayesh R, Mitchell SC, Idle JR, Smith RL. A genetic polymorphism of the
N-oxidation of trimethylamine in humans. Clin Pharmacol Therap 1987;42:588–
594.
Baker MT, Van Dyke RA. Reductive halothane metabolite formation and halothane
binding in rat hepatic microsomes. Chem-Biol Interact 1984;49:121–132.
Burk RF. Selenium-dependent glutathione peroxidases. In: Guengerich FP, editor.
Biotransformation, Vol. 3, Comprehensive Toxicology, first ed. Elsevier Science,
Oxford; 1997. p 229–242.
REFERENCES 31