CYP2D6 Overview and Genetic Implications
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Questions and Answers

What percentage of Europeans were found to exhibit slow metabolism?

  • 90%
  • 10% (correct)
  • 1%
  • 50%

    • The enzyme responsible for metabolizing debrisoquine was initially termed ______ based on emerging evidence.

    desbrisoquine and sparteine hydroxylase

    Early research into CYP2D6 utilized rat liver models exclusively, proving effective in replicating human enzyme isoforms.

    False (B)

    What was the groundbreaking discovery made by Urs Meyer and colleagues in the late 1980s?

    <p>The existence of gene polymorphisms in human CYP2D6.</p> Signup and view all the answers

    Match the researchers and their contributions to the understanding of CYP2D6.

    <p>Robert Smith = Identified individuals with exaggerated responses to debrisoquine Urs Meyer = Showed gene polymorphisms in CYP2D6 using Southern blot experiments Balant and Dayer = Developed antibodies to CYP2D6 and cloned human cDNA Researchers in the early 1990s = Sequenced DNA from individuals and identified two mutations in CYP2D6</p> Signup and view all the answers

    Which of the following are considered common substrates for CYP2D6? (Select all that apply)

    <p>Antidepressants (B), Cardiovascular agents (C), Antipsychotics (D)</p> Signup and view all the answers

    The majority of individuals in the European population are classified as poor metabolizers for CYP2D6.

    <p>False (B)</p> Signup and view all the answers

    What is the typical distance between the basic nitrogen and the site of oxidation in CYP2D6 substrates?

    <p>5-7 Angstroms</p> Signup and view all the answers

    Most mutations in CYP2D6 lead to either ______ defects or ______ resulting in truncated proteins or no protein synthesis.

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    What percentage of the population are identified as ultrarapid metabolizers (UMs) in the European population?

    <p>5.5% (B)</p> Signup and view all the answers

    Most individuals who are poor metabolizers (PMs) for CYP2D6 exhibit low plasma levels of drugs due to their inability to metabolize them.

    <p>False (B)</p> Signup and view all the answers

    Which common reaction is most frequently associated with CYP2D6?

    <p>Hydroxylation</p> Signup and view all the answers

    The typical distance of oxidation from basic nitrogen in CYP2D6 substrates is __________.

    <p>5-7 A</p> Signup and view all the answers

    Match the polymorphism with its corresponding CYP2D6 allele:

    <p>CYP2D6<em>3 = Point mutation leading to splicing defect CYP2D6</em>4 = Common loss of function allele CYP2D6<em>5 = Deletion causing no protein synthesis CYP2D6</em>6 = Common variant in poor metabolizers</p> Signup and view all the answers

    What is the primary impact of the polymorphisms found in CYP2D6?

    <p>Variation in drug efficacy (A)</p> Signup and view all the answers

    Only point mutations in CYP2D6 are responsible for its polymorphisms.

    <p>False (B)</p> Signup and view all the answers

    What was the significant finding from independent metabolism studies on desbrisoquine and sparteine in the mid-1970s?

    <p>Some individuals were unable to oxidize these drugs.</p> Signup and view all the answers

    What could explain the higher than expected morphine levels in breast milk after codeine use?

    <p>CYP2D6 gene duplication (C)</p> Signup and view all the answers

    Extensive metabolizers of codeine are less likely to suffer sedation than ultrarapid metabolizers.

    <p>True (A)</p> Signup and view all the answers

    What is the role of CYP2D6 in the metabolism of tamoxifen?

    <p>CYP2D6 produces the metabolite endoxifen, which is essential for tamoxifen's effectiveness.</p> Signup and view all the answers

    CYP2C19 is known as __________ hydroxylase.

    <p>mephenytoin</p> Signup and view all the answers

    Match the following CYP2C19 alleles with their activity status:

    <p>CYP2C19<em>2 = Poor metabolizer CYP2C19</em>17 = Increased activity CYP2C19<em>3 = Poor metabolizer CYP2C19</em>8 = Decreased activity</p> Signup and view all the answers

    Which of the following statements is true regarding clopidogrel?

    <p>It is a CYP2C19 substrate. (D)</p> Signup and view all the answers

    Higher levels of CYP2C19 activity are beneficial in treating GI disorders with PPIs.

    <p>False (B)</p> Signup and view all the answers

    What percentage of Europeans lack CYP2C19 activity?

    <p>3%</p> Signup and view all the answers

    CYP2D6*41 does not appear to affect __________ activity.

    <p>enzyme</p> Signup and view all the answers

    Tamoxifen primarily targets which type of cancer?

    <p>Hormone-positive breast cancer (C)</p> Signup and view all the answers

    Patients with two CYP2D6 poor metabolizer alleles have a lower incidence of breast cancer relapse.

    <p>False (B)</p> Signup and view all the answers

    Which CYP2C19 polymorphism is associated with a splicing defect leading to poor metabolism?

    <p>CYP2C19*2</p> Signup and view all the answers

    Omeprazole is a commonly used __________ drug that is metabolized by CYP2C19.

    <p>PPI</p> Signup and view all the answers

    Which allele is associated with faster than normal metabolism of drugs like omeprazole?

    <p>CYP2C19*17 (B)</p> Signup and view all the answers

    What polymorphism is most commonly associated with a truncated protein in CYP2D6?

    <p>CYP2D6*4 (C)</p> Signup and view all the answers

    CYP2D6*5 alleles result in no protein being synthesized.

    <p>True (A)</p> Signup and view all the answers

    What is the significance of the CYP2C19 gene in the context of metabolism?

    <p>CYP2C19 is associated with the absence of S-methylphentoin hydroxylase activity.</p> Signup and view all the answers

    The key restriction site for gene arrangements in CYP2D6 is called ___

    <p>Xba1</p> Signup and view all the answers

    Match the following CYP2D6 alleles with their effects:

    <p>CYP2D6<em>9 = Deletion of 3 lysine residues CYP2D6</em>10 = Proline to serine change CYP2D6<em>17 = Common in African populations CYP2D6</em>3 = Base deletion causing frameshift</p> Signup and view all the answers

    What is the result of having increased activity CYP2D6 alleles?

    <p>Faster metabolism (A)</p> Signup and view all the answers

    CYP2D6 polymorphisms have been successfully integrated into routine clinical practice.

    <p>False (B)</p> Signup and view all the answers

    What is the impact of having at least 3 copies of CYP2D6 in a patient?

    <p>Increased risk of opioid intoxication.</p> Signup and view all the answers

    The gene-dose effect demonstrated that heterozygotes for poor metabolizer alleles show ___ levels of activity.

    <p>lower</p> Signup and view all the answers

    Which of the following alleles is characterized by a base mutation from G to A leading to a premature stop codon?

    <p>CYP2D6*4 (B)</p> Signup and view all the answers

    Ultrarapid metabolizers are defined by having a single extra copy of CYP2D6 alleles.

    <p>False (B)</p> Signup and view all the answers

    What adverse effect can result from the ultrarapid phenotype of CYP2D6?

    <p>Life-threatening opioid intoxication.</p> Signup and view all the answers

    CYP2D6*10 is common in ___ populations.

    <p>East Asian</p> Signup and view all the answers

    What year was the CYP2C19 gene cloned?

    <p>1994 (D)</p> Signup and view all the answers

    The primary defect related to debrisoquine and sparteine polymorphism is the same as that of CYP2C19.

    <p>False (B)</p> Signup and view all the answers

    Flashcards

    CYP2D6 substrates

    Substrates for CYP2D6 are drugs with basic nitrogen that are ionized at physiological pH and have hydrophobic regions.

    CYP2D6 polymorphisms

    5-10% of individuals have polymorphisms in CYP2D6 genes that result in lack of enzyme activity.

    Common CYP2D6 substrates

    Common drugs processed by CYP2D6 include cardiovascular agents, antipsychotics, and antidepressants.

    Poor metabolizers (PMs)

    95% of Europeans are poor metabolizers of CYP2D6, having 2 copies of specific alleles.

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    Intermediate metabolizers

    Intermediate metabolizers may be heterozygous or homozygous for alleles associated with impaired metabolism, common in East Asians and Africans.

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    CYP2D6 function loss

    Most mutations in CYP2D6 involve point mutations or deletions leading to no protein or truncated proteins.

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    Genotyping for CYP2D6

    Genotyping is not routinely done despite its importance for determining drug dosage in 20-30% of the population metabolized by CYP2D6.

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    History of CYP450 enzymes

    CYP450 enzymes were discovered in the 1950s and identified to be multiple forms responsible for drug metabolism from the late 1960s.

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    CYP2D6

    A gene that encodes an enzyme for drug metabolism, affecting codeine and tamoxifen processing.

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    Codeine Analgesic Use

    Codeine is prescribed for pain relief but can lead to high morphine levels in breastmilk.

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    CYP2D6 Gene Duplication

    A genetic variation resulting in increased enzyme activity, leading to high morphine in breast milk.

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    Ultrarapid Metaboliser

    An individual with accelerated drug metabolism due to genetic variants, often leading to sedation from opioids.

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    Tamoxifen Mechanism

    Tamoxifen is metabolized by CYP2D6 to form endoxifen, which is effective against breast cancer.

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    CYP2C19 Role

    CYP2C19 is an enzyme that activates certain drugs and is influenced by genetic variation.

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    Poor Metabolizers

    Individuals who lack or have reduced function of a metabolic enzyme, affecting drug efficacy.

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    Clopidogrel Activation

    Clopidogrel requires CYP2C19 for activation; ineffective in individuals with defective alleles.

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    Omeprazole Efficacy

    Omeprazole effectiveness is increased in poor metabolizers due to higher drug levels.

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    CYP2C19 Polymorphism

    Variations in the CYP2C19 gene affecting drug metabolism efficiency.

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    CYP2C19*2 Allele

    A variant associated with poor metabolism found in multiple populations; splicing defect impacts enzyme function.

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    CYP2C19*17 Allele

    A polymorphism that increases CYP2C19 activity, leading to faster drug metabolism.

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    Benzodiazepines Substrates

    Drugs like diazepam are metabolized by CYP2C19; defects increase toxicity risk.

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    Escitalopram Metabolism

    Escitalopram is metabolized by CYP2C19, with variations affecting serum levels.

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    CYP2D6 Testing Importance

    Genotype testing for CYP2D6 can prevent adverse effects and optimize treatment with codeine and tamoxifen.

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    Debrisoquine

    A drug exclusively metabolized by CYP2D6, used to study metabolism defects.

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    Gene polymorphisms

    Variations in the CYP2D6 gene that affect drug metabolism.

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    CYP2D6 alleles

    Different versions of the CYP2D6 gene, affecting function and drug response.

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    Ultra-rapid metabolizers

    Individuals with multiple copies of CYP2D6 leading to faster drug processing.

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    CYP2D6*4 allele

    The most common defective allele of CYP2D6, leads to a truncated protein.

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    CYP2D6*5 allele

    An allele where the entire CYP2D6 gene is deleted, leading to no enzyme production.

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    Gene-dose effect

    The relationship between the number of active alleles and metabolic enzyme activity.

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    CYP2C19

    Another enzyme involved in drug metabolism, distinct from CYP2D6.

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    Codeine metabolism

    CYP2D6 metabolizes codeine into morphine, influencing its effectiveness.

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    CYP2D6*10 allele

    An allele common in East Asians that reduces the enzyme's catalytic activity.

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    CYP2D6*17 allele

    An allele found in African populations, associated with reduced enzyme activity.

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    Tandem repeats

    Multiple gene copies one after another in the chromosome.

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    Adverse drug reactions (ADR)

    Unwanted effects caused by medications, can be influenced by genetic factors.

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    Drug clearance

    The rate at which a drug is removed from the body, influenced by CYP2D6 activity.

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    Phenotype UMs

    Individuals with ultra-rapid metabolism potentially leading to insufficient drug response.

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    Pharmacogenetics

    The study of how genes affect a person’s response to drugs.

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    Study Notes

    CYP2D6

    • Substrate Characteristics: CYP2D6 substrates often have a basic nitrogen that ionizes at physiological pH and a hydrophobic region. Oxidation position is typically 5-7 Å from the basic nitrogen.

    • Genetic Polymorphisms: 5-10% of individuals lack CYP2D6 activity due to genetic variations (polymorphisms) in the gene. The majority of poor metabolizers in European populations have two copies of CYP2D6*3, *4, *5, or *6. A further 5% have other rare loss-of-function alleles.

    • Mutation Types: Most CYP2D6 mutations are point mutations leading to splicing errors or deletions resulting in truncated proteins or no protein synthesis.

    • Intermediate Metabolizers: Many individuals fall into the intermediate metabolizer category, especially in East Asian and African populations. This is often due to heterozygosity for inactivating mutations or homozygosity for alleles associated with impaired metabolism.

    • Drug Implications (Europe): Routine CYP2D6 genotyping for dose adjustments of substrates is not performed in ~5.5% of people who are Ultrarapid metabolizers (UMs) who have a rapid metabolism response resulting in too little drug in the body. ~7% who are poor metabolizers (PMs) experience adverse drug reactions (ADRs) as a result of high plasma levels. 20-30% of the population are metabolized by CYP2D6, but don't receive genotyping.

    CYP2D6 History

    • 1950s-1960s: Drug metabolism studies identified oxidative metabolism of drugs involving liver microsomes and molecular oxygen, NADPH. CYP450 discovery and initial characterization as a haemoprotein absorbing at 450 nm.

    • Mid 1970s: Studies of desipramine and sparteine metabolism highlighted individual variations in drug oxidation. Established that 10% of Europeans exhibited slow metabolism. CYP2D6 was identified as the key enzyme for metabolizing these drugs and some tricyclic antidepressants.

    • 1977: Debrisoquine and its metabolism demonstrated the link between individual variations in metabolizing drugs can lead to hypotension (exaggerated response)

    • 1980s: Rat liver-based studies produced antibodies and identified human cDNA, leading to a partial understanding of CYP2D6, but rat models have limitations.

    • 1980s - 1990s: Evidence of CYP2D6 gene polymorphisms emerged through Southern Blots. Researchers including Urs Meyer identified CYP2D6 polymorphisms by studying defects in drug metabolism linked to other conditions such as porphyria. Researchers in Geneva played a major role in improving methodology enabling CYP2D6 antibodies and human CYP2D6 cDNA cloning. RFLP's confirmed by subsequent research to identify allelic polymorphisms.

    • 1990s: Further DNA sequencing identified mutations/deletions. Alleles (e.g., duplications) and improved genotyping methods were discovered during this time.

    • 1993: Ultrarapid metabolizers were discovered with one or more additional copies of the CYP2D6 gene. Individual studies revealed the importance of the CYP2D6 genotypes in treatment response outcomes regarding other drug substrates e.g., anticonvulsant S-mephenytoin to highlight the independent defect of CYP2C19.

    CYP2D6 Gene Arrangements & Variants

    • Xba1 Restriction Site: Xba1 restriction sites help define the CYP2D6 arrangements. The distance between these sites changes based on gene deletions or duplications.
    • CYP2D6*3: A 6986-base deletion causes a frameshift mutation, resulting in incorrect amino acids and a premature stop codon.
    • CYP2D6*4: A G to A base change in intron 3 disrupts exon 4 splicing, leading to a truncated protein.
    • CYP2D6*5: An entire CYP2D6 gene is deleted, resulting in no protein synthesis.
    • CYP2D6*6: A nucleotide change (T to G) causes a frameshift mutation. Affects 4th least common poor metabolizer alleles.

    CYP2D6 Alleles Affecting Activity

    • Decreased/Increased Activity: Alleles that reduce/increase activity include CYP2D6*9, *10, *17. *9 has a deletion of 3 lysine residues and *10 has a proline-to-serine change. *17, which is a polymorphism in the upstream control region.

    • Increased Activity: Increased activity is associated with gene duplication. Ultrarapid metabolizers may have 1-13 copies of CYP2D6.

    • Clinical Significance: The number of active CYP2D6 alleles correlates strongly with enzyme activity, important for optimizing drug dose. Early on, CYP2D6 genotyping was not routinely used despite identification of many mutations over 30 years ago and genotyping became more accessible over 20 years ago.

    CYP2D6 Clinical Examples and Future

    • Examples: Recent cases illustrate the clinical importance of CYP2D6: e.g., infant death due to a breastfeeding mother taking high doses of codeine (Koren et al., 2006) illustrates the potential danger of ultrarapid metabolism. Patients who are poor metabolizers might not experience the drug response.
    • Future: The drug industry and guidelines could improve by avoiding development of drugs highly impacted by CYP2D6 genetic variations.

    CYP2C19

    • Characteristics: Lower in liver concentrations than CYP2D6; few but clinically important substrates. Plays a role in drug metabolism, activation of cyclophosphamide. CYP2C19 is known as mephenytoin hydroxylase. Genetic variations impacting drug metabolism were discovered in the early 1980s.

    • Polymorphisms: 3% of Europeans, 20% of Asians lack CYP2C19 activity. Other alleles with absent/decreased activity have been discovered.

    • Common Variants Affecting Activity: Several CYP2C19 alleles (e.g., *2, *3, *4) are associated with reduced or absent activity (truncated protein production).

    • CYP2C19 Clinical Examples: Poor metabolizers of this enzyme often show improved treatment response to proton pump inhibitors (PPIs) due to increased drug levels in the plasma which increases healing rate for gastric ulcers (Klotz, 2006).

    • Omeprazole: Patients lacking CYP2C19 activity show improved response to the treatment of peptic ulcers by Omeprazole.

    • Clopidogrel: Reduced effectiveness in individuals with defective alleles, impacting activation of this pro-drug.

    • Benzodiazepines: (e.g., Diazepam, Clobazam) are substrates and may cause toxicity/over-sedation in individuals with defective CYP2C19 variants

    • Anti-depressants: Citalopram and Escitalopram are metabolized through CYP2C19 and can have higher parent drug serum levels with variant alleles

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    Description

    This quiz covers the key aspects of CYP2D6, including its substrate characteristics, genetic polymorphisms, mutation types, and implications for drug metabolism. Understand how genetic variations in CYP2D6 affect drug response, especially in different populations. Test your knowledge of this important pharmacogenomic enzyme.

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