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

Figure 5–8. Structure of the protonated form of a mutant of
LacY. Two units of six-membrane-spanning α-helices (shown as
ribbons) are present. Substrate (depicted as green and black
balls) is bound to the interface of the two units and in the middle
of the membrane. Structure has been redrawn from coordinates
in Protein Data Bank (http://www.rcsb.org/pdb/).
families. The family name provides a description of
the function(s) of each family. However, some caution
should be exercised in interpretation of family
names because individual family members may have
vastly different specificities or functional roles
(Hediger, 2004).
Transporters in the SLC superfamily transport diverse
ionic and non-ionic endogenous compounds and xenobiotics.
SLC superfamily transporters may be facilitated transporters or
secondary active symporters or antiporters. The first SLC family
transporter was cloned in 1987 by expression cloning in Xenopus
laevis oocytes (Hediger et al., 1987). Since then, many transporters
in the SLC superfamily have been cloned and characterized
functionally. Predictive models defining important characteristics
of substrate binding and knockout mouse models
defining the in vivo role of specific transporters have been constructed
for many SLC transporters (Chang et al., 2004; Ocheltree
et al., 2004).
ABC Superfamily. ABC transporters can be divided into
seven groups based on their sequence homology:
ABCA (12 members), ABCB (11 members), ABCC (13
members), ABCD (4 members), ABCE (1 member),
ABCF (3 members), and ABCG (5 members). ABC
genes are essential for many cellular processes, and
mutations in at least 13 of these genes cause or contribute
to human genetic disorders (Table 5–3). In addition
to conferring multidrug resistance (Sadee et al.,
1995), an important pharmacological aspect of these
transporters is xenobiotic export from healthy tissues.
In particular, MDR1/ABCB1, MRP2/ABCC2, and
BCRP/ABCG2 have been shown to be involved in
overall drug disposition (Leslie et al., 2005). ABC
transporters including MDR1, BCRP, and MRP4 play
pivotal roles in the blood-tissue barriers in the brain,
placenta, testis, and retina. Active efflux against concentration
gradient in the blood-to-tissue direction on
the blood-facing plasma membranes limits the tissue
penetration from the blood.
101
CHAPTER 5
MEMBRANE TRANSPORTERS AND DRUG RESPONSE
Gated Pore Mechanism
Rocker Switch Mechanism
Na +
Glucose
Glucose
Figure 5–9. Alternating access models of the transport function of two transporters. The gated pore represents the model for SGLT
in which the rotation of two broken helices facilitates alternating access of substrates to the intracellular and extracellular sides of the
plasma membrane. The rocker switch represents the model by which MFS proteins, such as LacY, work. This example models a facilitated
glucose transporter, GLUT2.