CYP2A6 Overview and Alleles
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Questions and Answers

Which of the following is NOT a substrate of CYP2A6?

  • Disulfiram
  • Ibuprofen (correct)
  • Valproic acid
  • Halothane

    • CYP2A6 is the major enzyme responsible for metabolizing nicotine to cotinine.

    True (A)

    What is the primary function of CYP2A6 in the metabolism of coumarin?

    Coumarin hydroxylase

    The CYP2A6*2 allele is characterized by the ______ mutation, which prevents haem incorporation.

    <p>L160H</p> Signup and view all the answers

    Which CYP2A6 allele is most commonly associated with a complete lack of enzyme activity in the Asian population?

    <p>CYP2A6*4 (D)</p> Signup and view all the answers

    Match the CYP2A6 alleles with their primary characteristics:

    <p>CYP2A6<em>2 = L160H mutation, no haem incorporation CYP2A6</em>3 = Hybrid with CYP2A7 pseudogene CYP2A6<em>4 = Large deletion, no enzyme synthesis CYP2A6</em>5 = C479V mutation, unstable protein</p> Signup and view all the answers

    What type of mutation is associated with CYP3A7*3?

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

    CYP3A7 is expressed at lower levels in the liver than CYP3A5.

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

    What is the primary effect of the CYP3A7*1C polymorphism on DHEA metabolism?

    <p>It favours DHEA over DHEA sulfate with a 4-fold preference.</p> Signup and view all the answers

    CYP3A7*1L results from mRNA containing 13 exons of CYP3A7 and 2 additional exons from ______.

    <p>CYP3AP1</p> Signup and view all the answers

    Match the following CYP3A alleles to their descriptions:

    <p>CYP3A7<em>2 = No significant difference in DHEA metabolism CYP3A7</em>3 = Frameshift mutation CYP3A7<em>1C = Favors DHEA metabolism CYP3A7</em>1L = Contains 13 exons with unique splicing</p> Signup and view all the answers

    The findings from Basci et al, 2007 indicated a relationship between DHEAS levels and which condition?

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

    PXR acts as a transcriptional repressor for CYP3A4.

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

    Which test was used to obtain data related to CYP3A activity involving erythromycin?

    <p>Erythromycin breath test</p> Signup and view all the answers

    CYP1A1 is typically detectable only in individuals exposed to an ______.

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

    Which polymorphism is always seen together due to linkage disequilibrium?

    <p>-25385 and -24113 (B)</p> Signup and view all the answers

    What enzyme activity is catalyzed by CYP1A1?

    <p>Ethoxy resorufin O-de-ethylase (EROD) (C)</p> Signup and view all the answers

    Polymorphisms in the coding region of CYP1A1 have been shown to correlate with induced activity.

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

    What are the codon positions of polymorphisms detected in the Ah receptor?

    <p>Arg554Lys and Val570Ile</p> Signup and view all the answers

    The presence of the variant codon 554 allele correlates with high induced CYP1A1 ______ activity.

    <p>CYP1A1</p> Signup and view all the answers

    Match the following terms with their descriptions:

    <p>CYP1A2<em>F = Contains 163C&gt;T mutation influencing enzyme inducibility CYP1A2</em>1K = Relatively rare CYP1A2 variant 3-methylcholantrene = AhR inducer used to study CYP1A1 LNCaP = Prostate cancer cell line with methylated CYP1A1 regulatory region</p> Signup and view all the answers

    Which study analyzed caffeine consumption related to genetic variants?

    <p>Cornelis et al, 2011 (A)</p> Signup and view all the answers

    Aberrant methylation can affect local chromatin structure in cancer cells.

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

    What is the effect of the -729C>T mutation in CYP1A2?

    <p>It abolishes the binding site for an Eta nuclear factor, resulting in decreased CYP1A2 expression.</p> Signup and view all the answers

    CYP1B1 has an especially long _____ that suggests potential mRNA regulation.

    <p>3'UTR</p> Signup and view all the answers

    Which of the following enzymes is silenced due to hypomethylation of the CYP1B1 promoter in prostate cancer?

    <p>CYP1A1 (B)</p> Signup and view all the answers

    Which CYP variant is associated with the impaired metabolism of warfarin?

    <p>CYP2C9 R144C (C)</p> Signup and view all the answers

    CYP3A4 is expressed at high levels in the liver and metabolizes a wide range of drugs.

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

    What is the frequency of CYP3A4*22 allele in the population?

    <p>5%</p> Signup and view all the answers

    CYP3A4 is responsible for the metabolism of drugs such as ________, ________, and _________.

    <p>Cyclosporin, Erythromycin, Nifedipine</p> Signup and view all the answers

    Match the following CYP variants with their characteristics:

    <p>CYP2C9 R144C = Impaired metabolism of warfarin CYP3A5<em>1 = Normal hepatic expression of CYP3A5 CYP3A4</em>1B = Decreased gene expression associated allele CYP3A4*22 = Lower mRNA and protein levels</p> Signup and view all the answers

    What is the predictive factor for the expression of CYP3A5?

    <p>Polymorphic site in intron 3 (D)</p> Signup and view all the answers

    CYP3A7 is expressed significantly before 50 days of gestation.

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

    What effect does the CYP3A4*2 allele have on nifedipine metabolism?

    <p>Slightly less efficient</p> Signup and view all the answers

    CYP3A5*3 results in the creation of an ________ splice site.

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

    Match the following CYP variants with their impact:

    <p>CYP3A5<em>6 = Abnormal splicing CYP3A5</em>7 = Frameshift mutation CYP3A4<em>1B = Decreased binding of nuclear proteins CYP3A7</em>2 = Higher activity than CYP3A7*1</p> Signup and view all the answers

    How does the presence of T in intron 6 of CYP3A4 affect mRNA expression?

    <p>Decreases mRNA expression (C)</p> Signup and view all the answers

    Individuals homozygous for CYP3A4*22 show zero enzyme activity.

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

    What drug is mentioned in connection with altered CYP3A5 activity in Tanzanians?

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

    CYP3A4 polymorphisms can explain ________ variation in enzyme activity.

    <p>inter-individual</p> Signup and view all the answers

    Flashcards

    CYP3A7*2

    A genotype variant of CYP3A7, showing no significant difference in DHEA metabolism.

    CYP3A7*3

    A frameshift mutation variant of CYP3A7 affecting metabolic function.

    CYP3A7*1L

    A variant resulting from mRNA splicing, includes CYP3A7 and CYP3AP1 exons.

    CYP3A7*1C

    A polymorphism enhancing DHEA metabolism in adults over DHEAS.

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    PXR polymorphism

    Genetic variations in the PXR gene affecting CYP3A4 expression.

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    DHEA preference

    CYP3A7*1C has a 4-fold preference for DHEA metabolism over DHEAS.

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    DHEAS and osteoporosis

    Lower levels of DHEAS are linked to osteoporosis in elderly patients.

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    CYP3A activity variation

    The variability in CYP3A activity is not fully understood; rare alleles play a role.

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    Linkage disequilibrium

    Genetic correlation where certain polymorphisms are inherited together.

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    Andrews et al, 2010 study

    Investigated PXR gene expression using HepG2 cells with luciferase constructs.

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    CYP1A1

    A gene that encodes an enzyme involved in drug metabolism and carcinogen activation.

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    3-methylcholantrene

    An AhR inducer used to stimulate CYP1A1 in research studies.

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    Ah receptor

    A receptor mediating the induction of CYP1A1 by various compounds.

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    Polymorphism

    Variations in genes that may affect enzyme activity or traits.

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    CYP1A1 induction polymorphism

    Genetic variations that potentially influence the induction of CYP1A1 levels.

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    CYP1B1

    Another cytochrome P450 enzyme with potential regulation via miRNAs.

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    miR-27b

    A microRNA that has complementary sites in CYP1B1's 3'UTR, suggesting regulation.

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    CYP1A2

    A cytochrome P450 enzyme that shows variability in enzyme activity related to caffeine metabolism.

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    GWAS

    Genome-wide association study; a study that identifies genetic variants linked to traits or diseases.

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    CpG island methylation

    Regions of DNA important for gene regulation that can be modified by methylation.

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    CYP2A6 polymorphisms

    Genetic variations affecting CYP2A6 activity in humans.

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    CYP2A6*2 allele

    A CYP2A6 variant leading to no enzyme activity due to a mutation.

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    CYP2A6*4 allele

    A major deletion polymorphism causing no enzyme synthesis, common in East Asians.

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    CYP2B6*28

    A variant causing protein truncation, reducing enzyme functionality.

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    CYP2C8

    A P450 enzyme involved in drug metabolism and cardiovascular processes.

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    CYP2C8*2 allele

    A variant prevalent in African populations that reduces enzyme activity.

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    CYP2C9

    An important liver enzyme metabolizing various drugs with significant pharmacokinetic variability.

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    CYP2C9*2 allele

    A genetic variant that shows reduced metabolic activity in Caucasians.

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    CYP2C9*3 allele

    A variant associated with more severe loss of CYP2C9 function.

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    Warfarin

    A common medication whose metabolism is affected by CYP2C9 variants.

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    Amino acid substitutions

    Changes in the protein sequence due to genetic variance affecting enzyme efficacy.

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    Polymorphism impact on drug metabolism

    Genetic variations contribute to individual drug metabolism rates.

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    Cytochrome P450

    A family of enzymes involved in drug metabolism.

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    CYP2C9 R144C variant

    A genetic variant affecting warfarin metabolism, increasing adverse effects risk.

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    CYP3A4 Polymorphism

    Variations influencing CYP3A4 enzyme activity across individuals.

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    CYP3A5 variation in populations

    Different frequencies of CYP3A5 variants across ethnic groups.

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    Heterozygosity

    Presence of different alleles at a gene locus, affecting expression levels.

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    Substrate

    A substance upon which an enzyme acts.

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    Xenobiotics

    Chemical substances foreign to a biological system, often drug metabolites.

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    Study Notes

    CYP2A6

    • Relatively minor hepatic expression among P450 enzymes
    • Also known as nicotine C oxidase, cloned by Gonzalex and colleagues in 1989
    • Substrates include halothane, valproic acid, disulphiram, and nicotine (major pathway to cotinine)
    • Also metabolizes procarcinogens like aflatoxin and nitrosamines, and coumarin (found in food and perfume, broken down by coumarin hydroxylase)
    • Genetic polymorphisms are associated with absence of coumarin-7-hydroxylase activity. Around 0.2% of Europeans and 3% of East Asians lack CYP2A6 activity.
    • Some evidence suggests CYP2A6 duplication.

    CYP2A6 Alleles with Decreased Activity

    • CYP2A6*2 (L160H): No haem incorporation, relevant to Europeans.
    • CYP2A6*3: Hybrid between CYP2A6 and CYP2A7 pseudogene.
    • CYP2A6*4: Large deletion, no enzyme production, major PM allele in East Asians.
    • CYP2A6*5 (C479V): Unstable protein, rare allele.
    • Alleles with deletions likely due to meiotic exchange, resulting in multiple copies. No splicing defects reported.

    CYP2A6 Alleles with Increased Activity

    • Evidence of additional wild-type CYP2A6 copies in some individuals.
    • CYP2A6*1B: 3'-flanking region gene conversion with CYP2A7, leading to faster nicotine metabolism

    CYP2B6

    • Previously considered less important, now emphasized for environmental chemical metabolism.
    • CYP2B628, CYP2B66, CYP2B616, CYP2B618, CYP2B6*4. These are associated with lower expression and activity, or higher Vmax values (in vitro and in vivo).
    • Limited pharmacogenetic knowledge to predict metabolism capacity. Most alterations consistently observed in vitro; haplotype characterisation necessary before clinical predictions.

    CYP2C8

    • Located on chromosome 10q24, expressed primarily in the liver, crucial for metabolizing drugs related to diabetes, cancer, and malaria
    • Also oxidizes arachidonic acid for cardiovascular roles
    • Lower than CYP2C9, but higher than CYP2C19 expression levels.
    • Molecular mechanisms still not completely understood

    CYP2C8 Polymorphisms

    • CYP2C8*2: Primarily in African populations. In vitro expression reduced by 55% and Km for amodiaquine increased using paclitaxel.
    • CYP2C8*3 (K399R, R139K): Two amino acid substitutions. In vitro, reduced activity with paclitaxel and arachidonic acid, but no difference with amiodarone metabolism. Paclitaxel metabolism 15-75% of wild-type values (Dai et al, 2001). Mainly in Caucasians.
    • CYP2C8*4 (Ile264Met): Low activity, mainly in Caucasians. Not expressed in heterologous systems.
    • CYP2C8*5: Truncated protein.
    • CYP2C8*1B: Binds to nuclear factors.

    CYP2C9

    • Involved in 20% of hepatic CYP content, 10% drug metabolism
    • Important for warfarin, tolbutamide, sulphonyl ureas, NSAIDs (ibuprofen, diclofenac), and phenytoin (more important than CYP2A6); trimodal metabolism observed in 1979.
    • Polymorphisms discovered in 1979 related to amino acid substitutions and function, confirmed with warfarin patients in 1990s.

    CYP2C9 Variant Alleles

    • Most alleles show reduced activity.
    • CYP2C9*2 (Arg144Cys - 10% Europeans, primarily Caucasians).
    • CYP2C9*3 (Ile359Leu): Most detrimental; stronger pharmacokinetic effects than *2 (8% Europeans, primarily Caucasians). Discovered by Joyce and Don by sequencing genomic DNA.
    • Other alleles include CYP2C94 (Ile359Thr), CYP2C95 (Asp360Glu), CYP2C96 (Del A818, frameshift - inactive, rare). CYP2C911 (Arg335Trp).
    • Polymorphisms associated with narrow therapeutic window drugs (warfarin, phenytoin).
    • Significant contribution (10-20%) to warfarin dose variability, alongside VKORC1 genotype contributions (20-30%).

    CYP3A Subfamily

    • CYP3A4: Most important member, high liver expression, metabolises many drugs (cyclosporin, erythromycin, nifedipine, steroids).
    • CYP3A5: Expressed in about 20% of livers.

    CYP3A4 Polymorphisms

    • Some variants associated with non-synonymous mutations, but low population frequencies.
    • Upstream polymorphism (position 289) suggested to be associated with decreased gene expression (CYP3A4*1B, not consistently confirmed in vitro studies). Lower quinine metabolism in carriers compared to *1A. Decreased binding of nuclear proteins (PXR, NR1I2).
    • CYP3A42 (Ser222Pro), CYP3A422 (intron 6 polymorphism).

    CYP3A5 Polymorphism

    • Around 90% Europeans, 75% Asians and 20% Africans lack CYP3A5 expression.
    • *3 allele associated with a 6986A insertion. - This leads to an aberrant splice site and a nonfunctional protein.
    • *1 allele has normal expression.
    • Heterozygous (*1/*3 genotype) associated with CYP3A5 expression.
    • *6 and *7 result in abnormal splicing/frameshift, explaining expression absence in some African Americans (8-17% frequency).

    CYP3A7

    • Fetal enzyme, expressed from 2 months gestation to 6 months post-natal. Essential for metabolizing endogenous substrates (steroids, retinoic acid) and xenobiotics. High trans-retinoic acid metabolising ability (atRA), compared to CYP3A4,CYP3A5 and involved in treating acute promyelocytic leukaemia (APL)
    • CYP3A72 (T409R) moderate activity; CYP3A73: frameshift; CYP3A71L: formed by splicing; CYP3A71C : 4-fold preference for DHEA over DHEAS. Decreased DHEAS in elderly and associated with osteroporosis

    CYP3A Pharmacogenetics

    • Variable CYP3A activity may be partly explained by CYP3A5 expression and PXR gene regulation.

    PXR Polymorphism

    • PXR (CYP3A4 transcriptional regulator) polymorphisms screened for in known phenotypes. Some coding region amino acid changes affect transactivation, low frequencies. Upstream and intron polymorphisms. Phenotypes sometimes correlate with certain non-coding polymorphisms.
    • Polymorphism correlates with induced CYP1A1 activity

    CYP1A1 Pharmacogenetics

    • Extrahepatic, usually only detectable in inducer exposures (eg tobacco smoke). Individuals vary in inducing ability. Assessed by inducing lymphocytes with inducers and measuring CYP1A1 activity.

    CYP1A1 Induction Polymorphism

    • Amino acid substitutions in the coding region of CYP1A1 don't correlate with induced/uninduced activity. Upstream polymorphisms also don't correlate. CYP1A1 induction mediated by Ah receptor.

    Ah Receptor Polymorphism

    • Polymorphisms at Arg554Lys and Val570Ile in the Ah receptor. Arg554Lys polymorphism correlates with high induced CYP1A1 activity.
    • GWAS related to caffeine consumption and a strong correlation with AhR SNP.

    Prostate Cancer

    • CYP1A1 silenced in prostate cancer (LNCaP) lines due to CYP1B1 promoter hypomethylation.
    • Altered chromatin structure associated with AhR/ARNT complex inability to interact with CYP1A1 sites

    CYP1B1

    • Transcript with long 3'UTR. Possible mRNA regulation by miRNAs given potential sites for miRNA regulation.

    CYP1A2 Polymorphism

    • Caffeine GWAS suggests inter-individual variation in CYP1A2. Most significant CYP1A2 SNP within the promoter region (also intron 1).
    • CYP1A2*F contains a mutation that influences inducibility: Decreased CYP1A2 expression and caffeine metabolism found in some African populations.
    • Ah receptor polymorphisms also affects caffeine intake.

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    Description

    This quiz explores the CYP2A6 enzyme, its role in metabolizing various substances, and genetic polymorphisms affecting its activity. You'll learn about different alleles associated with decreased CYP2A6 function, their implications in various populations, and the history of its discovery. Test your knowledge of this important enzyme in pharmacogenetics.

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