Term
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Pharmacogenetics/Pharmacogenomics |
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Definition
| the study of genetically controlled variations in drug response, and includes both genetic polymorphisms & rare genetic defects that alter an individual's drug response |
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Term
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Definition
| a Mendelian or monogenetic trait that exists in the population in at least 2 phenotypes, neither of which is rare |
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Term
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Definition
| an organism's observable characteristics or traits |
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Term
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Definition
| the genetic makeup of a cell, an organism, or an individual |
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Term
def
extensive (fast) metabolism |
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Definition
| phenotype of persons that metabolize substances quickly |
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Term
def
Poor (slow) metabolizer |
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Definition
| phenotype of persons that metabolize substances slowly |
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Term
def
SNPs (single nucleotide polymorphism) |
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Definition
a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual.
variant sequence has a frequency of at least 1% in the population |
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Term
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Definition
a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual.
variant sequence has a frequency of less than 1% in the population |
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Term
| What are the 3 patterns of genetic polymorphisms? |
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Definition
Additive
Autosomal Recessive
Austosomal Dominant |
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Term
| What pattern of genetic polymorphism is most common? |
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Definition
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Term
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Additive (Co-dominant) |
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Definition
There is no domination of one allele over the other.
AA - Dark skin
Aa - Tan skin
aa - White skin
(an example only, not for real) |
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Term
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Definition
Normal allele dominates over mutant allele
AA - black skin
Aa - black skin
aa - white skin
(example only, not for real) |
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Term
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Definition
mutant allele dominates over normal allele
AA - black skin
Aa - white skin
aa - white skin
(example only, not for real) |
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Term
| What cytosolic enzyme is affected by acetylation polymorphism? |
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Definition
| N-acetyltransferase-2 (NAT2) |
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Term
| What cytosolic enzyme is affected by acetylation polymorphism? |
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Definition
| N-acetyltransferase-2 (NAT2) |
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Term
| What 2 enzymes catalyze acetylation? |
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Definition
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Term
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Definition
| Yes (originally thought not) |
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Term
| What does NAT2 catalyze acetylation of? |
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Definition
| lg. # of drugs & environmental chemicals s.a. procainamine, caffeine, and 4-aminobiphenyl (bladder carcinogen) |
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Term
| Is there ethnic variation in regards to acetylation polymorphism? |
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Definition
| considerable variation. Slow acetylators accounting for <10% to >90% in certain groups |
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Term
| What 3 clinically important consequences are associated with slow acetylation? |
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Definition
1) more prone to polyneuropathy during isoniazid treatment
2) more likely to develop hemolytic anemia in sulfa drug Tx
3) higher incidence of bladder cancer in those exposed to arylamine carcinogens |
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Term
| What do fast acetylators need to achieve a desired effect? |
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Definition
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Term
| What controls human acetylation polymorphism? |
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Definition
| 4 major alleles at a single autosomal gene locus on chromosome 8 |
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Term
| How many of the 4 alleles controlling human acetylation polymorphism encode for slow activity? |
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Definition
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Term
| Is fast or slow activity dominant in acetylation? |
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Definition
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Term
| Since fast acitivity is dominant, how many slow alleles must a person have to be a slow acetylator? |
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Definition
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Term
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Definition
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Term
| What metabolizes isomiazid? |
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Definition
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Term
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Definition
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Term
| What is the dose required of debrisoquine to lower bp? |
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Definition
| variable throughout the population |
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Term
| Why is there variation in debrisoquine metabolism? |
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Definition
| variation in the ability to hydroxylate debrisoquine to 4-hydroxydebrisoquine |
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Term
| What metabolizes debrisoquine? |
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Definition
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Term
| What is the population frequency for debrisoquine metabolism? |
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Definition
| bimodal: extensive or poor |
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Term
| What is the phenotypic variation among ethnic groups for debrisoquine metabolizers? |
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Definition
| Poor metabolizers: as high as 12% in Caucasians or as low as 1% in Arabic populations |
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Term
| Do poor or extensive metabolizers of debrisoquine have higher plasma concentrations of debrisoquine? |
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Definition
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Term
| What controls hydroxylation of debrisoquine? |
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Definition
| 2 alleles at a single autosomal gene locus on chromosome 22 |
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Term
| What alleles have been identified in poor metabolizers of debrisoquine? |
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Definition
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Term
| What is noted about CYP2D6 levels in poor metabolizers of debrisoquine? |
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Definition
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Term
| Why are genetic differences in CYP2D6 importanat? |
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Definition
| a number of drugs are metabolized by this enzyme |
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Term
| When is CYP2D6 polymorphism clinically important? |
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Definition
1) drug metabolized by it
2) widely used drug
3) narrow therapeutic window |
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Term
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Definition
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Term
| Why is ADH polymorphism important? |
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Definition
| Each ADH allele encodes for a different isoenzyme. Each isoenzyme has it's own kinetic properties which all vary greatly in Km & Vmax |
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Term
| What 2 enzymes are needed in methyl conjugation? |
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Definition
| thiomethyltransferase & thiopurine methyltransferase |
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Term
| What drugs are methy transferases important in metabolizing? |
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Definition
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Term
| What happens if there's decreased methyltrasferase activity while using chemotherapeutic agents s.a. 6-mercaptopurine & azathiopurine? |
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Definition
| drug induced myelosuppression |
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Term
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Definition
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Term
| Is poor metabolism of mephenytoin recessive, dominant, or co-dominant? |
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Definition
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Term
| What ethnic group is at an increased risk for poor mephenytoin metabolism? |
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Definition
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Term
| What enzyme is responsible for mephenytoin hydroxylation? |
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Definition
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Term
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Definition
| catalyzes oxidation of polycyclic hydrocarbon |
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Term
| What are substrates for CYP1A1? |
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Definition
| environmental toxins, potential carcinogens, & certain drugs |
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Term
| What determines genetically controlled variability of CYP1A1? |
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Definition
| variation in inducibility of AHH activity |
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Term
| What does AHH activity induction require? |
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Definition
| intracellular receptor protein, Ah receptor |
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Term
| What determines the presence of the Ah receptor? |
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Definition
| polymorphism at the Ah locus |
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Term
| What happens once the inducing agent binds to the Ah cytosolic receptor? |
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Definition
| inducer-receptor complex gains chromatin-binding properties & binds to regulatory elements upstream of CYP1A1 on chromosome 15 |
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Term
| What does the inducer-receptor complex binding of regulatory elements upstream of CYP1A1 on chromosome 15 do? |
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Definition
| activation of gene transcription & induction of CYP1A1 |
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Term
| Is CYP1A1 induction also bimodal? |
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Definition
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Term
| What explains the interindividual susceptibility to potential carcinogens & other environmental pollutants that have been associated with cancer risk? |
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Definition
| the differences in induction od CYP1A1 |
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Term
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Definition
| Aryl Hydrocarbon Hydroxylase |
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Term
| What is the most common DNA sequence variations? |
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Definition
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Term
| Are SNPs more stable than repeated sequences? |
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Definition
| yes (therefore have lower mutation rate) |
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Term
| How often in the human genome as bases polymorphic? |
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Definition
| 1/100 bases (40-200 SNPs) |
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Term
| How have SNPs been used to etimate tribal migration & divergence of wthnic groups? |
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Definition
| SNPs have been found to segregate together |
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