Drug Metabolism in Drug Design and Development Basic Concepts and Practice

substrate kinetics, it appears that there may be multiple glucuronide transporters
on the ER membrane to move the glucuronide products from the lumen to the
cytoplasm by facilitated diffusion (ATP-independent) (Csala, 2004).

3.1.2 Endogenous Substrates

There are a large number of endogenous substrates for the UGTs. These
include bilirubin, the primary degradation product of heme (Fig. 3.3). In the
native state, bilirubin exists as a highly nonpolar conformation with internal
hydrogen bonds sequestering the two carboxyl groups. Once inside the

FIGURE 3.2 Localization of UGT enzymes in the endoplasmic reticulum. The active
site is located on the inside of the ER with a single transmembrane domain and a 25 a.a.
COOcytosolic tail. UDPGA is transported into the ER and istrans-stimulated by
UDPGlcNAC. Once the glucuronides are formed, they must be transported out of the
ER by a separate transport protein (depicted by flipping through the membrane).
Source: Adapted from Clarke DJ and Burchell B, The uridine diphosphate
glucuronosyltransferase multigene family: function and regulation. In: Conjugation-
Deconjugation Reactions in Drug Metabolism and Toxicity, F.C. Kaufman, editor,
New York, Springer-Verlag, 3.8: 1994.

Bilirubin

12 8

H 3 C(CH^2 )^2 (CH^2 )^2 CH 3

COO–COO–

N

H

N

H

N

H

N

H

O

H 3 C

O

CH 3

FIGURE 3.3 The structure of the UGT1A1 endogenous substrate, bilirubin.

UDP-GLUCURONOSYLTRANSFERASES 39