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MORE GENETICS OF PK AND PD Lecture #28

Inherited Variability Restricted to drug metabolism ~None with drug absorption, distribution, renal or biliary excretion – Exception: organic anion-transporting polypeptide 1B1 (OATP1B1)  pravastatin

Mutation Types Non-synonymous substitution – alters amino acid of protein synonymous substitution – “silent mutation” and degeneracy – doesn’t alter amino acid

Basic Genetics intron “Between Genes”

Inherited Variability in PK Oxidation – CYP2D6 – CYP2C9 – CYP2C19 – CYP3A S-methylation – Thiopurine methyltransferase (TMPT) Acetylation – N-acetyltranferase (NAT)

Oxidation: CYP2C9 African Pygmy

Oxidation: CYP2C9

Oxidation: CYP2C19 (PPI)

Oxidation: CYP2C19 Polymorphisms

Oxidation: CYP2C19

CYP2C19: Proton Pump Inhibitor Therapy

Oxidation: CYP3A

S-methylation: Thiopurine Methyltransferases (TPMT) SAM 6-thioguanine

S-methylation: Reaction 6-thioguanine 6-methylthioguanine TPMT S-adenosyl methionine S-adenosyl-L-homocysteine CH 3 antimetabolites (anticancer drug)

Polymorphisms

S-methylated Drugs Pharmacodynamics HGPRT= Hypoxanthine-guanine phosphoribosyltransferase immunosuppressant (organ transplantation) cancer, Crohn’s disease and ulcerative colitis Target inhibit cell proliferation leukemia Purine Biosynthesis

Conventional versus Individualized Individualized Conventional

Acetylation: N-acetyltransferases (NAT) Acetyl-CoA

General Reaction NAT R R

Reactions (Sim, 2008 Toxicology)

Families, Location and General Substrate Specificities NAT1 – everywhere – folate degradation – breast cancer NAT2 – Liver and Gut – sulfamethazine and arylhydrazine – isoniazid induced neurotoxicity and hydralazine-induced lupus (slow metabolizers) sulfamethazine (sulfonamide antibacterial) arylhydrazine

Genetics: Polymorphic Variants NAT2NAT1

NAT2 KatG = Bacterial Catalase-peroxidase InhA = Bacterial 2-trans-enoyl-acyl carrier protein reductase tuberculosis antibiotic

NAT2

Metabolic Profiling