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

GST
137
NH 2
COOH
O
NH
O –
vinyl sulfone derivative
S O
NH
O
active site
tyrosine residue
of GST
NH 2
COOH
COOH
O
O –
NH
H
O
O
O
S O
NH
O
P
Cl
Cl
N
N
Cl
Cl
COOH TLK286
Cl
Cl
O N
P
– O N
Cl
Cl
+ +
O N
– O
P
N
Cl
Cl
active alkylating agent
CHAPTER 6
DRUG METABOLISM
cellular damage
Figure 6-11. Generation of the reactive alkylating agent following the conjugation of glutathione to TLK286. GST interacts with the
prodrug and GSH analog, TLK286, via a tyrosine in the active site of GST. GSH portion is shown in red. The interaction promotes
β-elimination and cleavage of the prodrug to a vinyl sulfone and an active alkylating fragment. (See Townsend and Tew, 2003.)
ionizable amine is neutralized by the covalent addition
of the acetyl group. NATs are among the most poly morphic
of all the human xenobiotic drug-metabolizing
enzymes.
The characterization of an acetylator phenotype in
humans was one of the first hereditary traits identified,
and was responsible for the development of the field of
pharmacogenetics (see Chapter 7). Following the discovery
that isonicotinic acid hydrazide (isoniazid, INH)
could be used in the cure of tuberculosis, a significant
proportion of the patients (5-15%) experienced toxicities
that ranged from numbness and tingling in their fingers
to CNS damage. After finding that isoniazid was metabolized
by acetylation and excreted in the urine,
researchers noted that individuals suffering from the
toxic effects of the drug excreted the largest amount of
unchanged drug and the least amount of acetylated isoniazid.
Pharmacogenetic studies led to the classification
of “rapid” and “slow” acetylators, with the “slow” phenotype
being predisposed to toxicity. Purification and
characterization of N-acetyltransferase and the eventual
cloning of its RNA provided sequence characterization
of the gene, revealing polymorphisms that correspond
to the “slow” acetylator phenotype. There are two functional
NAT genes in humans, NAT1 and NAT2. Over 25
allelic variants of NAT1 and NAT2 have been characterized,
and in individuals in whom acetylation of drugs is
compromised, homozygous genotypes for at least two
variant alleles are required to predispose a patient to
lowered drug metabolism. Polymorphism in the NAT2
gene, and its association with the slow acetylation of isoniazid,
was one of the first completely characterized
genotypes shown to affect drug metabolism, thereby
linking pharmacogenetic phenotype to a genetic polymorphism.
Although nearly as many mutations have
been identified in the NAT1 gene as the NAT2 gene, the
frequency of the slow acetylation patterns are attributed
mostly to the polymorphism in the NAT2 gene.
Drugs that are subject to acetylation and their
known toxicities are listed in Table 6–4. The therapeutic
relevance of NAT polymorphisms is in avoiding druginduced
toxicities. The adverse drug response in a slow
acetylator resembles a drug overdose; thus, reducing
the dose or increasing the dosing interval is recommended.
Aromatic amine or a hydrazine groups exist in
many classes of clinically used drugs, and if a drug is