Podcast
Questions and Answers
What is the primary purpose of the monooxygenase activity of CYP enzymes?
What is the primary purpose of the monooxygenase activity of CYP enzymes?
Which of the following is NOT a function of CYP enzymes?
Which of the following is NOT a function of CYP enzymes?
Which family classification requires over 40% sequence identity among CYP enzymes?
Which family classification requires over 40% sequence identity among CYP enzymes?
Which CYP enzyme is predominantly involved in xenobiotic metabolism?
Which CYP enzyme is predominantly involved in xenobiotic metabolism?
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What factor can lead to individual differences in CYP profiles?
What factor can lead to individual differences in CYP profiles?
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How can drug-drug interactions impact drug therapy?
How can drug-drug interactions impact drug therapy?
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What is the average time and cost required for the drug design process from lead identification to clinical trials?
What is the average time and cost required for the drug design process from lead identification to clinical trials?
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Which phase of the drug design process focuses on the absorption, distribution, metabolism, excretion, and toxicity predictions?
Which phase of the drug design process focuses on the absorption, distribution, metabolism, excretion, and toxicity predictions?
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Which of the following CYP enzymes is involved in the metabolism of polycyclic aromatic hydrocarbons (PAHs)?
Which of the following CYP enzymes is involved in the metabolism of polycyclic aromatic hydrocarbons (PAHs)?
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What is a key active ingredient in guinea hen weed that inhibits the growth of several tumors?
What is a key active ingredient in guinea hen weed that inhibits the growth of several tumors?
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Which CYP enzyme family can be overexpressed in some cancers, such as lung cancer?
Which CYP enzyme family can be overexpressed in some cancers, such as lung cancer?
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What role can CYP1 inhibition play in, according to the text?
What role can CYP1 inhibition play in, according to the text?
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Study Notes
Drug Development Process
- The drug development process from lead identification to clinical trials takes >10 years and ~$2 billion USD on average, with a >95% failure rate.
- The process consists of:
- Discovery (1–∞ years)
- Preclinical research (~5 years)
- Clinical development (>5 years)
- Review (~1 year)
- Market approval and launch
- Post-market monitoring (phase IV)
Clinical Development
- Clinical development consists of three stages:
- Safety (~50 healthy patients, ~1 year)
- Proof of concept (~250 target patients, ~2 years)
- Regulatory evidence (>1000 target patients, >2 years)
In Silico Methods
- In silico methods can accelerate the drug development process in terms of time, labor, and cost.
- Applications of in silico methods include:
- Hit identification
- Target identification
- Lead optimization
- ADMET predictions
- Virtual patient modeling
Cytochrome P450 Enzymes
- CYP enzymes are majorly found in the endoplasmic reticulum of the liver.
- There are over 7000 CYP proteins, with 57 known CYPs encoded by the human genome.
- CYPs are categorized into families (>40% sequence identity) and subfamilies (>55% sequence identity).
- CYPs contain a haem group, responsible for activating molecular oxygen, along with an electron from CYP reductase.
- CYPs are responsible for making compounds more hydrophilic.
CYP Reactions
- CYP reactions include:
- Aromatic hydroxylation
- Deamination
- N-dealkylation
- O-dealkylation
- Aliphatic hydroxylation
- N-oxidation
- Sulfoxidation
CYPs and Drug Metabolism
- CYPs are responsible for the metabolism of >80% of drugs.
- Xenobiotics do not exclusively comprise clinical drugs.
- The main CYPs involved in xenobiotic metabolism are:
- CYPs 1A1/2, 2A6, 2B6, 2C8/9, 2C18/19, 2D6, 2E1, and 3A4/5
- CYPs are a major consideration in drug development.
- Drugs can be substrates, inducers, and/or inhibitors of CYP enzymes.
Clinical Importance
- Genetic differences can lead to individual CYP profiles.
- Environmental factors, age, and disease can also alter CYP profile.
- Drug–drug and drug–herb interactions can lead to unexpected effects as a function of altered CYP activity.
- Therapeutic index: efficacy, safety in terms of dose and window.
Molecular Modelling
- Molecular modelling can be used to predict CYP inhibition.
- The CYP1 family is involved in the metabolism of polycyclic aromatic hydrocarbons (PAHs).
- CYP1 enzymes are overexpressed in some cancers (e.g., lung).
- CYP1 inhibition can play a role in chemoprevention.
Research Question
- Can the activities of CYP1 enzymes be selectively blocked using natural products to prevent cancer?
- One commonly used plant is Petiveria alliacea (guinea hen weed), which potently inhibits the growth of several tumours.
- The key active ingredient is dibenzyl trisulfide (DTS), a moderate inhibitor of a wide range of CYP enzymes, including carcinogen-activating members of the CYP1 family.
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Description
Explore the fascinating world of Cytochrome P450 (CYP) enzymes, prominently found in the endoplasmic reticulum of the liver. Learn about the structure, function, and classification of the over 7000 CYP proteins, which play a crucial role in drug metabolism and detoxification.
