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

fractions of circulating catecholamines, estrogens, iodothyronines, and
DHEA exist in the sulfated form.
Some human SULTs display great fidelity to unique substrate
specificities; other SULTs are shockingly promiscuous in their activities.
The SULT1 family isoforms are considered to be the major
forms involved in xenobiotic metabolism, with SULT1A1 being
quantitatively and qualitatively the most important in the liver. It displays
extensive diversity in its capacity to catalyze the sulfation of a
wide variety of structurally heterogeneous xenobiotics with high
affinity. SULT1 isoforms have been recognized as phenol SULTs,
since they catalyze the sulfation of phenolic molecules such as acetaminophen,
minoxidil, and 17α-ethinyl estradiol. SULT1B1 is similar
to SULT1A1 in that it can sulfate a very wide range of compounds,
although it is much more abundant in the intestine than the
liver. While three SULT1C isoforms exist in humans, little is known
about their substrate specificity toward drugs or other compounds. In
rodents, SULT1C enzymes are capable of sulfating the hepatic carcinogen
N-OH-2-acetylaminofluorene, and are responsible for the
bioactivation of this and related carcinogens. Their role in this pathway
in humans is not clear. SULT1C enzymes are expressed abundantly
in human fetal tissues, yet decline in abundance in adults.
SULT1E catalyzes the sulfation of endogenous and exogenous
steroids, and has been found localized in liver, as well as in hormoneresponsive
tissues such as the testis, breast, adrenal gland, and placenta.
In the upper GI tract, SULT1A3 and SULT1B1 are particularly
abundant.
The conjugation of drugs and xenobiotics is considered
primarily a detoxification step, assuring that these compounds enter
the aqueous compartments of the body and are targeted for elimination.
However, drug metabolism through sulfation often leads to the
generation of chemically reactive metabolites, where the sulfate is
electron withdrawing and may be heterolytically cleaved, leading to
the formation of an electrophilic cation. Most examples of the
generation by sulfation of a carcinogenic or toxic response
in animal or test mutagenicity assays have been documented
with chemicals derived from the environment or from heterocyclic
arylamine food mutagens generated from well-cooked meat. Thus,
it is important to understand whether genetic linkages can be made
by associating known human SULT polymorphisms to cancers that
are believed to originate from environmental sources. Since
SULT1A1 is the most abundant SULT form in human tissues and
displays broad substrate specificity, the polymorphic profiles associated
with this gene and their associations with various human
cancers is of considerable interest. Recently, gene copy number polymorphisms
within the SULT1A1, SULT1A3, and SULT1A4 genes
have been indentified, which may help explain much of the interindividual
variation in the expression and activity of these enzymes.
Knowledge of the structure, activities, regulation, and polymorphisms
of the SULT superfamily will aid in understanding of the
linkages between sulfation and cancer susceptibility, reproduction,
and development. Sulfation is a major xenobiotic metabolizing system
during human development, with levels of many enzymes higher
in the fetus than the adult.
The SULTs from the SULT1 and SULT2 families were
among the first xenobiotic-metabolizing enzymes to be crystallized,
and the data indicated a highly conserved catalytic core (Negishi
et al., 2001). Crystal structures of the different SULTs indicate that
while conservation in the PAPS binding region is maintained, the
organization of the substrate binding region differs, helping to
X
(substrate)
GST
H 2 N
H 2 N
COOH
COOH
explain the observed differences in catalytic potential displayed with
the different SULTs.
Glutathione Conjugation. The glutathione-S-transferases
(GSTs) catalyze the transfer of glutathione to reactive
electrophiles, a function that serves to protect
cellular macromolecules from interacting with electrophiles
that contain electrophilic heteroatoms
(-O, -N, and -S) and in turn protects the cellular environment
from damage (Hayes et al., 2005). The co-substrate
in the reaction is the tripeptide glutathione, which
is synthesized from γ-glutamic acid, cysteine, and
glycine (Figure 6–9). Glutathione exists in the cell as
oxidized (GSSG) or reduced (GSH) forms, and the ratio
of GSH:GSSG is critical in maintaining a cellular environment
in the reduced state. In addition to affecting
xenobiotic conjugation with GSH, a severe reduction
in GSH content can predispose cells to oxidative damage,
a state that has been linked to a number of human
health issues.
In the formation of glutathione conjugates, the
reaction generates a thioether linkage with drug or
xenobiotic to the cysteine moiety of the tripeptide.
Characteristically, all GST substrates contain an electrophilic
atom and are hydrophobic, and by nature will
associate with cellular proteins. Since the concentration
of glutathione in cells is usually very high, typically
~7 μmol/g of liver, or in the 10 mM range, many drugs
and xenobiotics can react non-enzymatically with glutathione.
However, the GSTs have been found to
occupy up to 10% of the total cellular protein concentration,
a property that assures efficient conjugation
of glutathione to reactive electrophiles. The high
concentration of GSTs also provides the cells with a
sink of cytosolic protein, a property that facilitates
O
H
N
GSH
X-GSH
O
SH
N
H
S-X
COOH
COOH
Figure 6–9. Glutathione (GSH) as a co-substrate in the conjugation
of a drug or xenobiotic (X) by glutathione-S-transferase
(GST).
O
H
N
O
N
H
135
CHAPTER 6
DRUG METABOLISM