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

Table 5–3
The ATP Binding Cassette (ABC) Superfamily in the Human Genome and Linked Genetic Diseases
GENE FAMILY NUMBER OF
NAME NAME FAMILY
MEMBERS EXAMPLES OF LINKED HUMAN DISEASES
ABCA ABC A 12 Tangier disease (defect in cholesterol transport; ABCA1), Stargardt
syndrome (defect in retinal metabolism; ABCA4)
ABCB ABC B 11 Bare lymphocyte syndrome type I (defect in antigen-presenting;
ABCB3 and ABCB4), progressive familial intrahepatic cholestasis
type 3 (defect in biliary lipid secretion; MDR3/ABCB4), X-linked
sideroblastic anemia with ataxia (a possible defect in iron
homeostasis in mitochondria; ABCB7), progressive familial
intrahepatic cholestasis type 2 (defect in biliary bile acid excretion;
BSEP/ABCB11)
ABCC ABC C 13 Dubin-Johnson syndrome (defect in biliary bilirubin glucuronide
excretion; MRP2/ABCC2), pseudoxanthoma (unknown mechanism;
ABCC6), cystic fibrosis (defect in Cl − channel regulation; ABCC7),
persistent hyperinsulinemic hypoglycemia of infancy (defect in
inwardly rectifying K + conductance regulation in pancreatic B cells;
SUR1)
ABCD ABC D 4 Adrenoleukodystrophy (a possible defect in peroxisomal transport or
catabolism of very long-chain fatty acids; ABCD1)
ABCE ABC E 1
ABCF ABC F 3
ABCG ABC G 5 Sitosterolemia (defect in biliary and intestinal excretion of plant sterols;
ABCG5 and ABCG8)
urine or bile, ABC transporters are expressed in the polarized tissues
of kidney and liver: MDR1, MRP2, and MRP4 (ABCC4) on the
brush-border membrane of renal epithelia; MDR1, MRP2, and
BCRP on the bile canalicular membrane of hepatocytes; and MRP3
and MRP4 on the sinusoidal membrane of hepatocytes. Some ABC
transporters are expressed specifically on the blood side of the
endothelial or epithelial cells that form barriers to the free entrance
of toxic compounds into tissues: the BBB (MDR1 and MRP4 on the
luminal side of brain capillary endothelial cells), the bloodcerebrospinal
fluid (CSF) barrier (MRP1 and MRP4 on the basolateral
blood side of choroid plexus epithelia), the blood-testis barrier
(MRP1 on the basolateral membrane of mouse Sertoli cells and
MDR1 in several types of human testicular cells), and the bloodplacenta
barrier (MDR1, MRP2, and BCRP on the luminal maternal
side and MRP1 on the anti-luminal fetal side of placental trophoblasts).
Substrate Specificity of ABC Transporters. MDR1/ABCB1 substrates
tend to share a hydrophobic planar structure with positively
charged or neutral moieties (see Table 5–4 and Ambudkar et al.,
1998). These include structurally and pharmacologically unrelated
compounds, many of which are also substrates of CYP3A4, a major
drug-metabolizing enzyme in the human liver and GI tract. Such
overlapping substrate specificity implies a synergistic role for MDR1
and CYP3A4 in protecting the body by reducing the intestinal
absorption of xenobiotics (Zhang and Benet, 2001). After being
taken up by enterocytes, some drug molecules are metabolized by
CYP3A4. Drug molecules that escape metabolic conversion are
eliminated from the cells by MDR1 and then reenter the enterocytes.
The intestinal residence time of the drug is prolonged with the aid of
MDR1, thereby increasing the chance of local metabolic conversion
by the CYP3A4 (see Chapter 6).
MRP/ABCC Family. The substrates of transporters in the MRP/ABCC
family are mostly organic anions. The substrate specificities of
MRP1 and MRP2 are similar: both accept glutathione and
glucuronide conjugates, sulfated conjugates of bile salts, and
non-conjugated organic anions of an amphipathic nature (at least one
negative charge and some degree of hydrophobicity). They also
transport neutral or cationic anticancer drugs, such as vinca alkaloids
and anthracyclines, possibly by means of a cotransport or symport
mechanism with reduced glutathione (GSH).
MRP3 also has a substrate specificity that is similar to that of
MRP2 but with a lower transport affinity for glutathione conjugates
compared with MRP1 and MRP2. Most characteristic MRP3 substrates
are monovalent bile salts, which are never transported by
MRP1 and MRP2. Because MRP3 is expressed on the sinusoidal
side of hepatocytes and is induced under cholestatic conditions,
backflux of toxic bile salts and bilirubin glucuronides into the blood
circulation is considered to be its physiological function.