DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 5–1
Regulation of Transporter Expression by Nuclear Receptors (Continued)
TRANSCRIPTION
TRANSPORTER SPECIES FACTOR LIGAND (DOSE) EFFECT
MRP4 mouse CAR Phenobarbital (100mg/kg, ↑ Expression in liver and kidney
3 days)
TCPOBOP
(3mg/kg, 4 days)
PPARα Clofibrate (500mg/kg, ↑ Expression in liver
10 days)
OATP1B1 human SHP1 Cholic acid indirect effect on HNF1α expression
PXR Rifampin ↑ Expression in human hepatocye
OATP1B3 human FXR Chenodeoxycholate ↑ Expression in Hepatoma cells
Oatp1a4 rat PXR Pregnenolone 16α- ↑ Expression in liver
carbonitrile (75 mg/kg,
4 days)
CAR Phenobarbital (80 mg/kg, ↑ Expression in liver,
5 days) ↑ hepatic uptake of digoxin
mouse PXR Pregnenolone 16α- ↑ Expression in liver
carbonitrile (75 mg/kg,
CAR
3 days)
Phenobarbital (100mg/kg,
3 days)
TCPOBOP (3mg/kg, 3 days) ↑ Expression in liver
BSEP human FXR Chenodeoxycholate ↑ Transcription activity (promoter assay)
Ntcp rat SHP1 Cholic acid ↓ RAR mediated transcription
OSTα/β human FXR Chenodeoxycholate/ ↑ Transcription activity (promoter assay)
GW4064
FXR Chenodeoxycholate ↑ Expression in ileal biopsies
mouse FXR GW4064 (30 mg/kg, ↑ Expression in intestine and kidney
twice daily, 4 days)
MDR2 mouse PPARα Ciprofibrate (0.05% w/w ↑ Expression in the liver
in diet)
See Geick et al., 2001; Greiner et al., 1999; Kok et al., 2003.
Sodium Galactose Transporter (vSGLT). vSGLT is a sodium galactose
transporter of Vibrio parahaemolyticus. vSGLT is a member of
the solute sodium symporters (SSS). This bacterial transporter is
~30% homologous to the human SGLT1, an important transporter
for the intestinal absorption of sugars. Crystal structure at ~3 Å resolu -
tion suggests that like LacY, vSGLT operates as an alternating-access
transport mechanism (Faham et al., 2008). However, vSGLT
operates as a gated pore rather than a rocker switch mechanism
(Figure 5–9) (Kanner, 2008; Karpowich and Wang, 2008). The
12 transmembrane domains consist of two symmetrical halves
(six domains each). Galactose and sodium are bound at the center of
the membrane at two broken helices, one from each of the symmetrical
halves. These broken helices appear to rotate to achieve alternating
access of extracellular and intracellular sides. This mechanism,
though similar to LacY, involves less molecular dynamic changes
than LacY, which operates as a rocker switch. Figure 5–9 shows an
alternating access model for SGLT (Karpowich and Wang, 2008).
In this model, a binding pocket faces the extracellular side. The
substrate, glucose, is bound to this binding pocket. Movement of a
bundle of helices, triggered by binding of glucose and sodium,
simultaneously closes the access of the binding pocket to the extracellular
face and opens the exit pathway to the intracellular spaces.
The model is based on symmetrical arrangement of helices.
TRANSPORTER SUPERFAMILIES
IN THE HUMAN GENOME
Two major gene superfamilies play critical roles in the
transport of drugs across plasma and other biological
membranes: the SLC and ABC superfamilies. Web sites
that have information on these families include
http://nutrigene.4t.com/humanabc.htm (ABC superfamily),