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Questions and Answers
All of the following are correct about every cytochrome P450 EXCEPT:
All of the following are correct about every cytochrome P450 EXCEPT:
Conversion of cholesterol to steroid hormones in the adrenal gland involves:
Conversion of cholesterol to steroid hormones in the adrenal gland involves:
Which of the following best describes cholesterol?
Which of the following best describes cholesterol?
Cytochromes P450 are mainly associated with lipid bilayers.
Cytochromes P450 are mainly associated with lipid bilayers.
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Which of the following families of Cytochromes P450 are involved in processing environmental contaminants, food additives and drugs?
Which of the following families of Cytochromes P450 are involved in processing environmental contaminants, food additives and drugs?
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The major function of Cytochromes P450 is to make xenobiotics more water soluble for excretion via kidneys or in bile.
The major function of Cytochromes P450 is to make xenobiotics more water soluble for excretion via kidneys or in bile.
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Which reaction type does the cytochrome P450-mediated hydroxylation of ibuprofen at its alkyl side chain fall under?
Which reaction type does the cytochrome P450-mediated hydroxylation of ibuprofen at its alkyl side chain fall under?
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CYP3A4 is found in the gastrointestinal tract and liver and is responsible for the poor bioavailability of many drugs due to its ability to hydroxylate them to inactive forms.
CYP3A4 is found in the gastrointestinal tract and liver and is responsible for the poor bioavailability of many drugs due to its ability to hydroxylate them to inactive forms.
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What is the function of the spectrophotometric assay in the context of cytochrome P450 activity?
What is the function of the spectrophotometric assay in the context of cytochrome P450 activity?
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What is the primary cause of substrate inhibition in cytochrome P450-catalyzed reactions?
What is the primary cause of substrate inhibition in cytochrome P450-catalyzed reactions?
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Drug-drug interactions can be explained by the presence of a cavernous pocket adjacent to the heme cofactor in cytochrome P450 enzymes.
Drug-drug interactions can be explained by the presence of a cavernous pocket adjacent to the heme cofactor in cytochrome P450 enzymes.
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Individuals with high levels of CYP2E1 are at a higher risk for hepatitis as a reaction to anesthesia due to the potential for liver damage caused by the enzymes.
Individuals with high levels of CYP2E1 are at a higher risk for hepatitis as a reaction to anesthesia due to the potential for liver damage caused by the enzymes.
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The increased levels of CYP2E1 in response to chronic alcohol is an example of decreased cytochrome P450 expression.
The increased levels of CYP2E1 in response to chronic alcohol is an example of decreased cytochrome P450 expression.
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What is a cytochrome P450 polymorphism?
What is a cytochrome P450 polymorphism?
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CYP2C9 is responsible for the metabolism and elimination of S-warfarin from the body.
CYP2C9 is responsible for the metabolism and elimination of S-warfarin from the body.
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Individuals with the CYP2C9*3 variant may require a higher dose of warfarin to maintain therapeutic blood levels.
Individuals with the CYP2C9*3 variant may require a higher dose of warfarin to maintain therapeutic blood levels.
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What is pharmacogenetics?
What is pharmacogenetics?
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The Roche AmpliChip CYP450 Test aims to provide clinicians with information on the activity of CYP2D6 and CYP2C19 gene products.
The Roche AmpliChip CYP450 Test aims to provide clinicians with information on the activity of CYP2D6 and CYP2C19 gene products.
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It is recommended to memorize specific pathways and molecular structures related to Cytochromes P450.
It is recommended to memorize specific pathways and molecular structures related to Cytochromes P450.
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Study Notes
Cytochromes P450
- Cytochromes P450 are a unique family of heme proteins, encoded by a gene superfamily, with hundreds of members.
- They are enzymes that catalyze monooxygenation reactions.
- These reactions involve incorporating one oxygen atom (from O₂) into an organic molecule.
- Endogenous substrates include cholesterol, steroid hormones, fatty acids, prostaglandins.
- Exogenous substrates include drugs, food additives, pesticides, chemicals that enter the body through ingestion, inhalation, and absorption through the skin.
- These enzymes play significant roles in medicine, including the inactivation or activation of therapeutic agents and drug-drug interactions.
- They contribute to personalized medicine opportunities.
Lecture 1
- Introduction to Cytochrome P450 enzymes: This lecture introduces the fundamental concepts of Cytochrome P450 enzymes.
- Metabolism of Endogenous and Exogenous Molecules: This covers the role of P450s in processing endogenous and exogenous molecules.
- Induction and Inhibition of Cytochromes P450: This examines how P450 activity can influenced by various factors, including the induction or inhibition of P450 activity.
Lecture 2
- The catalytic mechanism of Cytochromes P450: This lecture provides in depth study into the catalytic mechanism of cytochromes P450 enzymes.
Learning Outcomes Lecture 1
- Recognize the general form of mono-oxygenation reactions catalyzed by P450s.
- Distinguish Class I and II P450s.
- Demonstrate understanding of the classification of the P450 superfamily.
- Define major categories of P450 function in humans.
- Show an understanding of spectrophotometric assays for quantifying P450 activity.
- Describe and identify the nature of drug-drug interactions.
- Demonstrate understanding of the significance of polymorphisms in human P450s.
Cytochrome P450 Electron Transport Systems (additional info)
- Most mammalian P450s are found in the endoplasmic reticulum (ER) within hepatocytes, renal cells, and cells of the respiratory tract. These are the class II Cytochrome P450 enzymes.
- Class I cytochrome P450 enzymes are found within mitochondria.
- NADPH/NADP+ is a redox co-substrate.
- Flavin is a 2 x 1e redox cofactor.
- Heme is a 1e redox cofactor.
- These are powerful tools and identify consequences of polymorphisms and consequences of drug interactions.
Human Cytochromes P450
- There are 57 cytochromes P450s in humans.
- CYP1, CYP2, CYP3, CYP4, CYP11, CYP17, CYP19, CYP21, and CYP26 are some of the most important types.
- Seven P450s are mitochondrial.
Cytochromes P450 for Processing Endogenous Molecules
- P450s with high substrate specificity process cholesterol, steroids, prostaglandins, and fatty acids.
- Reactions catalyzed by CYP11A1 in adrenal mitochondria are covered in the slides.
Steroid Hormone Synthesis in the Adrenal Gland
- Illustrates the synthesis of steroid hormones in the adrenal gland, highlighting the key roles of various CYP enzymes.
- The process often involves a series of reactions involving various cytochrome P450s in distinct locations in the cells, and are summarised well in the figures.
All of the following are correct about every cytochrome P450 EXCEPT
- Option D is the incorrect statement.
Conversion of Cholesterol to Steroid Hormones in the Adrenal Gland Involves
- Option A is correct.
Which of the following best describes cholesterol?
- Option B (lipid) is the correct answer.
Cytochromes P450 are Membrane Associated
- The substrates are generally hydrophobic.
- They are soluble in lipid bilayers.
Cytochromes P450 Processing Xenobiotics 1 and 2
- P450s involved in processing exogenous molecules (xenobiotics - like drugs, food additives, etc) are less substrate-specific.
- These enzymes evolved to make lipophilic toxins more hydrophilic for excretion.
- Many xenobiotics are lipophilic and accumulate in cells. Metabolism to hydrophilic products is required for excretion.
Cytochromes P450 Processing Xenobiotics 3
- Shows various types of reactions catalyzed by cytochromes P450: Hydroxylation, O-demethylation, N-demethylation, aromatic hydroxylation. This shows different types of reactions catalysed by P450s.
Cytochromes P450 and Metabolism of Therapeutic Drugs
- CYP3A4 is present in GI tract and liver and plays a significant role in metabolizing drugs.
- The high specificity of CYP enzymes leads to various drugs being processed by multiple CYPs at different sites.
- It shows different percentage of drugs metabolized by different CYPs.
Quantifying CYP Catalytic Activity
- One substrate of all P450 reactions changes color when converted to the product.
- Using spectrophotometry to measure the color change, the reaction rate can be calculated.
- These assays are important tools for characterizing CYP activities and assessing the consequences of polymorphisms and drug interactions.
Steady-State Assay of Cytochromes P450
- Includes description of methods and apparatus, along with calculations to find rate of reaction.
Substrate Inhibition of Cytochromes P450
- Substrate inhibition kinetics for two reactions catalyzed by CYP 3A4 are shown.
- This shows how the reaction rate decreases as substrate concentration increases.
Substrate Inhibition: A Special Case of Competitive Inhibition
- This expands on the concept of substrate inhibition, illustrating it as a specific case of competitive inhibition.
- The graph depicts how reaction velocity depends on substrate concentration.
Moderated Drug Efficacy 1: Substrate Inhibition and Drug-Drug Interactions
- Explains drug-drug interactions through substrate inhibition in the active site pocket.
Moderated Drug Efficacy 2: Regulation of CYP Expression
- Explains how compounds like anaesthetics and anti-depressants can increase CYP2E1 levels.
- Higher levels of CYP2E1 increase risk of hepatitis after surgery for these patients when the drugs are metabolized.
Moderated Drug Efficacy 3: CYP Polymorphisms
- Polymorphism describes difference in DNA sequences found in populations.
- In some groups genetic variations have a consequence on varying rates of metabolizing individual drugs.
- Illustrates the concept of CYP2C9 and its polymorphism in relation to warfarin, and its effect on dosage.
Pharmacogenetics- how genes influence an individual's response to drugs
- This illustrates that genes affect individual response to drugs, leading to drug toxicity in some individuals and not in others, with a common drug dose. This suggests variations must be considered for personalized prescriptions.
Pharmacogenetics and Personalized Prescriptions
- Detailed knowledge of P450s can lead to personalised prescriptions.
- Roche AmpliChip CYP450 Test aids clinicians in determining the therapeutic strategy and dose for drugs metabolized by CYP2D6 or CYP2C19.
- Illustrates pharmacogenomics and CYP enzymes in relation to poor metabolizers and normal metabolizers.
References (Page 38)
- Provides a list of key research papers and books related to the study of cytochromes P450 and their role in biology and medicine.
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