3.1.1 Location Within the Cell
The active site of the UGTs face the lumen of the endoplasmic reticulum
(Fig. 3.2), whereas the active site of P450, also microsomal enzymes, faces the
cytosolic side. Nonpolar substrates can diffuse through the ER membrane and
be conjugated in the ER lumen. However, UDPGA must be transported into
the ER and the resulting glucuronide products generally need to be transported
out of the ER into the cytosol (Bossuyt, 1994a and 1994b). There istrans-
stimulation of UDPGA influx by UDP-N-acetylglucosamine (UDPGlcNAC),
UDP-xylose, and UDP-glucose (Bossuyt, 1996). Transport proteins for
glucuronides have been characterized on the hepatocyte sinusoidal membrane,
bile canalicular membrane, and in kidney tubules. In the hepatocyte,
glucuronides are transported through the sinusoidal membrane by MRP3. On
the bile canalicular membrane, the major transporter is MRP2. Based on
Overall reaction:+UGTUDP-glucuronic acidAcetaminophen
glucuronideAcetaminophenUDPO_OOCHOOHOHH
O-P
O-O
O-P
O-OHO NH
O-CH 2
OHO OHNHNOOONH-COO CH^3COO–HOOHOHO-O
O-P O-P
O-O
O-CH 2
OHO OHNHNOOC– CH 3
O
FIGURE 3.1 The glucuronidation reactions. Enzyme: UDP glucuronosyltransferase
(UGT or UDPGT); Cosubstrate: uridene diphosphoglucuronic acid (UDPGA)-
activated cosubstrate.
38 CONJUGATIVE METABOLISM OF DRUGS