Transcript Gene related metabolism of drugs

Gene Related
Metabolism of
Drugs
Anastasios
Maratonitis
(2009)
There are more than 30 families of drug-metabolizing enzymes in
humans, and essentially all have genetic variants, many of
which translate into functional changes in the proteins
encoded. The cytochrome P-450 enzymes, a superfamily of
microsomal drug-metabolizing enzymes, are the most
important of the enzymes that catalyze phase I drug
metabolism. One member of this family, cytochrome P-450 2D6
(CYP2D6) will be used as example of gene variation in drug
metabolism. More than 75 CYP2D6 alleles have been
described, subjects with ultra rapid metabolism have been
proven to have multiple copies of this gene. Such subjects can
have an inadequate therapeutic response to standard doses of
the drugs metabolized by CYP2D6 (the higher the metabolic
ratio, the less metabolite is excreted). The effect of the number
of copies of the CYP2D6 gene — ranging from 0 to 13 — is well
visible on the pharmacokinetics of the antidepressant drug
nortriptyline shown in next figure
Mean plasma concentrations of nortriptyline after a single 25-mg oral dose are shown in subjects with 0,
1, 2, 3, or 13 functional CYP2D6 genes
ALTHOUGH THE OCCURRENCE OF MULTIPLE COPIES OF
THE CYP2D6 GENE IS RELATIVELY INFREQUENT AMONG
NORTHERN EUROPEANS, IN EAST AFRICAN POPULATIONS,
THE ALLELE FREQUENCY CAN BE AS HIGH AS 29 PERCENT
The table below lists common drug metabolism gene variants and their
frequencies in major ethnic groups.
Gene and Variant
Caucasians
African-Americans
Asians
CYP2D6*3
2%
0
0
CYP2D6*4
12-21%
2%
1%
CYP2D6*5
2-7%
4%
6%
CYP2D6*10
1-2%
6%
51%
CYP2D6*17
0
34%
0%
CYP2D6*2xN
1-5%
2%
0-2%
CYP2C9*2
8-14%
1%
0%
CYP2C9*3
4-16%
1-2%
2-3%
CYP2C9*5
-
1.7%
-
CYP2C9*6
-
0.6%
-
CYP2C19*2
15%
17%
30%
CYP2C19*3
0.04%
0.40%
5%
Adapted from Blue Cross Blue Shield Special report
The CYP2D6 polymorphism represents an excellent example of
both the potential clinical implications and the process by
which gene research led from the phenotype to an
understanding of molecular mechanisms at the level of the
genotype. Similar approaches were subsequently applied to
other families of drug-metabolizing enzymes. We now know
that many other drug-metabolizing enzymes display genetic
variation that can influence a person's response to a drug. The
table bellow lists selected examples of those, clinically
relevant, variations . In many cases, we also understand the
molecular basis of inherited variation in the drug-metabolizing
enzymes.
(GENE) DRUGS
metabolizers
CYP2C9
CYP2C19
CYP3A4/3A5/3A7
Dihydropyrimidine
Dehydrogenase
N-acetyltransferase
(NAT2)
Glutathione transferases
(GSTM1, GSTT1, GSTP1)
RESPONSES AFFECTED
Anticoagulant effect of warfarin
Peptic ulcer response to omeprazole
Efficacy of immunosuppressive effects of tacrolimus
Fluorouracil neurotoxicity
Hypersensitivity to sulfonamides, amonafide toxicity,
hydralazine-induced lupus, isoniazid neurotoxicity
Decreased response in breast cancer, more toxicity
and worse response in acute myelogenous leukemia
P-glycoprotein
(ABCB1)
Decreased CD4 response in HIV-infected
patients, decreased digoxin AUC, drug resistance in epilepsy
UGT2B7
COMT
CYP2B6
Thiopurine methyltransferase
(TPMT)
Morphine plasma levels
Enhanced Levodopa drug effect
Ovarian failure due to Cyclophosphamide
Thiopurine toxicity and efficacy,
risk of second cancers