Pharmacogenetics Overview

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Questions and Answers

Pharmacogenetics is the study of how genetic variations influence individual responses to drugs.

True (A)

The term 'pharmacogenetics' was first coined in which year?

1970

1932

1959 (correct)

1997

What is the name of the enzyme involved in breaking down drugs and other foreign compounds in the body?

Cytochrome P450 (CYP)

Individuals with ______ metabolizers have more than two active genes for CYP enzymes.

ultrarapid Signup and view all the answers

Match the following drugs with their associated adverse reactions:

Isoniazid = Peripheral neuritis Primaquine = Acute haemolysis Succinylcholine = Prolonged paralysis Signup and view all the answers

Which of the following is NOT a type of genetic polymorphism?

Gene duplication (A) Signup and view all the answers

What is the name of the gene responsible for the ability to taste phenylthiocarbamide?

TAS2R38 Signup and view all the answers

Copy number variations are DNA segments smaller than 1 kb with a variable number of copies.

False (B) Signup and view all the answers

The field of ______ aims to personalize drug therapy using information from the human genome project.

pharmacogenomics Signup and view all the answers

Which of the following statements accurately describes the relationship between pharmacogenetics and pharmacogenomics?

Pharmacogenetics is a branch of pharmacogenomics. (D) Signup and view all the answers

Which of the following is a consequence of pharmacogenetic polymorphisms?

Different responses to drugs (B) Signup and view all the answers

Synonymous mutations do not alter the amino acid sequence of the translated protein.

True (A) Signup and view all the answers

What are two general mechanisms by which DNA methylation can regulate gene expression?

Methylation of gene promoters may reject the binding of some transcription factors to their DNA binding sites. Transcriptional silencing capability of DNA methylation may occur via a complex indirect mechanism involving changes in chromatin conformation. Signup and view all the answers

The control of cytochrome P450 gene methylation primarily occurs at ______ sites in the mammalian genome.

CpG Signup and view all the answers

Match the following types of mutations with their descriptions:

Synonymous = A single nucleotide change in the coding region that does not alter the amino acid sequence of the translated protein Non-synonymous = Involve a change to the nucleotide sequence in the coding region that will result in an altered amino acid sequence, which may alter protein structure and will have a functional consequence Exon skipping = A type of mutation that results in the removal of an exon from the final mRNA transcript Whole gene deletion = Removal of an entire gene from the genome Signup and view all the answers

Which of the following is NOT an advantage of genotypic approaches in pharmacogenetic studies?

Can assess the functional effects of polymorphisms (C) Signup and view all the answers

Phenotypic approaches to pharmacogenetic studies can be limited by the availability of suitable probe drugs for analysis.

True (A) Signup and view all the answers

What are two examples of phenotypic approaches used in pharmacogenetic studies?

Enzyme activity measurements and analysis of drug metabolism patterns. Signup and view all the answers

A lack of response to a drug can occur if the target dose does not respond or if the drug is or too rapidly.

metabolized, excreted Signup and view all the answers

Which of the following is NOT a type of non-synonymous mutation?

Silent (B) Signup and view all the answers

Study Notes

Pharmacogenetics: A Historical Overview

Pharmacogenetics studies hereditary variations in drug responses.
German geneticist Friedrich Vogel first used the term in 1959, observing variable responses to drugs like isoniazid, primaquine, and succinylcholine in patients with hepatic porphyria.
Clinical data on variable responses to drugs existed before this, including those related to isoniazid, primaquine, and succinylcholine.
Drug metabolism is largely handled by CYPs, which are categorized into different groups based on their activity and genetic variability.
- Ultrarapid metabolizers possess multiple active CYP genes.
- Extensive metabolizers have two functional CYP genes.
- Poor metabolizers lack functional CYP enzymes due to defective genes.
- Intermediate metabolizers have one functional and one defective CYP gene, or two partially defective genes.
CYPs are responsible for 80% of phase 1 metabolism.

Pharmacogenomics: Expanding Personalized Medicine

Pharmacogenomics uses human genome information to personalize drug therapy.
Pharmacogenomics utilizes gene sequencing to select or develop drugs tailored to individual genetic makeups.
This field includes existing drugs and new drug development.
The term was coined in 1997.
Pharmacogenetics is a sub-speciality of pharmacogenomics.

Historical Highlights in Pharmacogenetics

Pythagoras (6th century BC): Observed adverse reactions to fava beans, now linked to variations in glucose-6-phosphate dehydrogenase (G6PD).
1932: Inability to taste phenylthiocarbamide (PTC) identified as genetically inherited, related to the TAS2R38 gene. This gene encodes a taste receptor protein.
1950s: Genetic polymorphisms in G6PD, cholinesterase, and acetylation identified. These are associated with adverse reactions to specific drugs
- Isoniazid (TB treatment): Slow acetylation is associated with peripheral neuritis.
- Primaquine (malaria treatment): Deficiency in G6PD causes acute haemolysis in some individuals.
- Succinylcholine (muscle relaxant): Deficiency in cholinesterase results in prolonged paralysis.
1970s: Cytochrome P450 polymorphisms described.
1980s onwards: Gene cloning allowed for identification of additional polymorphisms and correlations with phenotypes.
1990s-2000s: Human Genome Project provided further genome sequence data.
Present: Genome-wide association studies investigate disease susceptibility and drug response.

Genetic Polymorphisms

Genetic polymorphisms are mutations with a population frequency of at least 1 in 100.
Polymorphisms can be base substitutions (SNPs), insertions, or deletions and occur roughly every 1,000 bases.

Functional Polymorphisms

Functional polymorphisms affect biological activities due to
- Amino acid substitutions.
- Transcription factor binding site alterations.
- Splicing site mutations (e.g. exon skipping).
- Gene duplications or deletions.

Synonymous and Non-synonymous Mutations

Synonymous mutations don't alter amino acid sequences.
Non-synonymous mutations change amino acid sequences and potentially protein function. Examples include base insertions, deletions, missense, nonsense, and non-stop mutations.

Control of CYP Gene Expression

DNA methylation may regulate CYP gene expression. This mechanisms occurs primarily at CpG sites by DNA methyltransferase enzymes, and can affect transcription factor binding or transcriptional silencing.
MicroRNAs and changes in mRNA target binding sites or mRNA precursors can influence CYP expression.

Pharmacogenetic Polymorphisms: Consequences

Consequences of variations in drug responses include drug toxicity and lack of response.
- Toxicity: Exaggerated response or effect involves an inappropriate target, dependent on the drug's therapeutic window.
- Lack of response: insufficient drug activity or too-rapid drug metabolism/excretion or failure of prodrug activation; the target dose may not respond or drug may be metabolized/excreted too rapidly.

Identification Approaches

Phenotypic approaches:
- Measure enzyme activity or drug metabolite patterns.
- Problems include tissue accessibility, difficulty in studying drug receptors.
Genotypic approaches:
- Examine genes for polymorphisms.
- More common, due to extensive genome sequencing data (e.g., NOMAD). Data isn't always available for all populations.
- Advantages include direct gene examination, use of readily available DNA samples (blood, buccal cells, saliva). -Disadvantages include relating polymorphisms to function, which can be technologically complex.

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Description

Explore the historical context of pharmacogenetics, focusing on how genetic variations affect drug responses. Learn about key figures like Friedrich Vogel and the categorization of CYP enzymes that play a crucial role in drug metabolism. This quiz delves into the clinical relevance of hereditary factors in personalized medicine.