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BackgroundBackground :
• Clinical genetics• Cytogenetic• Somatic Cell Genetics• Biochmical genetics• Molecular genetics• Cancer genetics• Population genetics• Immunogenetics• Pharmacogenetics• Genetic toxicology• Developmental genetics• Behavior genetics
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I. Key Concepts and Terms
Monogenic: due to allelic variation at a single gene
Polygenic: due to variations at two or more genes
Polymorphic: frequently occurring monogenic variants occurring at a frequency >1%
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GENETIC POLYMORPHISMS
Pharmacokinetic Pharmacodynamic
•Transporters•Plasma protein binding•Metabolism
•Receptors•Ion channels•Enzymes•Immune molecules
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From: Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 286:487-491, 1999.
II. Genetic polymorphisms in drug metabolizing enzymes
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Genetic polymorphisms in drug metabolizing enzymes
• 1. Polymorph of debrisoquine• extensive metabolizer——EM• poor metabolizer ——PM*> 12.6• recessive transmission,autosomal
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DRUGS WHOSE METABOLISM CO-SEGREGATES WITH DEBRISOQUINE
alprenolol amitriptyline bufuralol clomipraminecodeine desipramine encainide ethylmorphineflecainide fluoxetine guanoxan imipraminemetoprolol nortriptyline paroxetine phenforminpropafenone propranolol
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3. Glucose-6-phosphate dehydrogenase activityEffects >300 million worldwide
R-NH2 CYP MPOPGH Synthase
R-NOH
ERYTHROCYTE
R-NOH
O2
HgbFe+2
R-NO HgbFe+3
Reactive Oxygen
NADH
NAD+MetHgbReductase
NADPHor GSH(?)
NADP+ or GSSG(?)HMP Shunt
G-6-PDDependent
SODCatalaseGSH Peroxidase
Detoxification
SplenicSequestration
Hemolytic Anemia
GSH
Semi-mercaptal
sulfinamide
R-NH2
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Drugs and Chemicals Unequivocally Demonstrated to Precipitate Hemolytic Anemia
in Subjects with G6PD Deficiency
Acetanilide Nitrofurantoin PrimaquineMethylene Blue Sulfacetamide Nalidixic AcidNaphthaleneSulfanilamide SulfapyridineSulfamethoxazole
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INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS
Ethnic Group Incidence(%)Ashkenazic Jews 0.4Sephardic Jews Kurds 53 Iraq 24 Persia 15 Cochin 10 Yemen 5 North Africa <4
Iranians 8Greeks 0.7-3
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INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS
Ethnic Group Incidence(%)Asiatics Chinese 2 Filipinos 13 Indians-Parsees 16 Javanese 13 Micronesians <1
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4. N-ACETYLTRANSFERASE ACTIVITY
Distribution of plasma isoniazid concentration in 483 subjectsafter and oral dose. Reproduced from Evans DAP. Br Med J 2:485, 1960.
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ETHNIC DIFFERENCES IN THE DISTRIBUTION OF ACETYLATOR PHENOTYPE
Population % Slow % Hetero Fast % Homo Fast
South Indians 59 35.6 5.4Caucasians 58.6 35.9 5.5Blacks 54.6 38.6 6.8
Eskimos 10.5 43.8 45.7Japanese 12 45.3 42.7Chinese 22 49.8 28.2
From: Kalo W. Clin Pharmacokinet 7:373-4000, 1982.
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XENOBIOTICS SUBJECT TO POLYMORPHIC ACETYLATION IN MAN
Hydrazines isoniazid hydralazine phenylzineacetylhydrazine hydrazine
Arylamines dapsone procainamide sulfamethazine sulfapyridineaminoglutethimide
Carcinogenic Arylamines benzidine-naphthylamine4-aminobiphenyl
Drugs metabolized to aminessulfasalazine nitrazepamclonazepam caffeine
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ADVERSE EFFECTS TO SULFASALAZINE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Data from: Das et al. N Engl J Med 289:491-495, 1973.
Side Effect cyanosis hemolysistransient reticulocytosis
Frequency of side effectSlow Acetylators Fast Acetylators
9 15 06 0
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0
20
40
60
80
100
120
0 20 40 60 80 100
Duration of Therapy (months)
% o
f p
ts w
ith
lup
us
Slow Acetylators
Fast Acetylators
Relationship Between Onset of Lupus Syndrome in Fast and Slow Acetylators Receiving Procainamide.
Data from: Woosley RL, et al. N Engl J Med 298:1157-1159, 1978.
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Distribution of acetylator phenotype in control subjects and those experiencing a sulfonamide
hypersensitivity reaction.Rieder et al. Clin Pharmacol Ther 49:13-17, 1991.
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NAT1N-acetyl-SMX
UDPGTSMX-glucuronide
CYP2C9MPOPGH SYNTHASE
SMX hydroxylamineNitrosoDetox
Covalent binding tocellular macromolecules/
cytotoxicity
Hypersensitivity/Adverse Reaction
O-acetylation
Acetoxy ester
NAT1Hydroxamicacid
N,O-AT
Detoxified metabolite
Sulfamethoxazole(SMX)
NO
NH2 S
O
O
HN
CH3
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Future Role of SNPs and Pharmacogenetics
SNP - Single Nucleotide Polymorphisms
……. G G T A A C T G …………. G G C A A C T G …...
AS of February 2001, 1.42 million SNPs had been identified in the human genome.