Cytochrome P450 Polymorphisms — MCQs
The cytochrome involved in monooxygenase-mediated detoxification of drugs is:
Which of the following is the platinum-based chemotherapeutic agent used as first-line treatment for ovarian carcinoma?
Match the following drugs in Column A with their contraindications in Column B. | Column A | Column B | | :-- | :-- | | 1. Morphine | 1. QT prolongation | | 2. Amiodarone | 2. Thromboembolism | | 3. Vigabatrin | 3. Pregnancy | | 4. Estrogen preparations | 4. Head injury |
Which of the following cytochromes is involved in monooxygenase mediated detoxification of drugs?
A lady gets pregnant even though she was on contraceptive pills. She is suspected to have consumed
Which of the following combinations can result in severe toxicity due to inhibition of cytochrome P450 enzymes?
Centrilobular necrosis of the liver may be seen with?
Chemical process involved in conversion of progesterone to glucocorticoids is
Drugs used for Prophylaxis of migraine include the following except?
Testing of HLA-B' 5701 is recommended prior to initiation of which antiretroviral agent?
Cytochrome P450 Polymorphisms Indian Medical PG Practice Questions and MCQs
Question 1: The cytochrome involved in monooxygenase-mediated detoxification of drugs is:
- A. Cyt P 450 (Correct Answer)
- B. Cytochrome b5
- C. Cytochrome c
- D. Cytochrome oxidase
Explanation: ***Cyt P 450*** - **Cytochrome P450 (CYP450)** enzymes are a superfamily of heme-containing monooxygenases primarily responsible for the **metabolism of xenobiotics**, including the detoxification of drugs. - They catalyze oxidation reactions, introducing a hydroxyl group to substrates, which typically increases their **hydrophilicity** and facilitates excretion. *Cytochrome c* - **Cytochrome c** is a component of the **electron transport chain** in mitochondria, primarily involved in cellular respiration and energy production. - It acts as an **electron carrier** between Complex III and Complex IV, not directly in drug detoxification. *Cytochrome b5* - **Cytochrome b5** participates in various metabolic reactions, including **fatty acid desaturation** and cholesterol biosynthesis, and can sometimes assist CYP450 enzymes. - However, it does not function as a primary monooxygenase for drug detoxification itself. *Cytochrome oxidase* - **Cytochrome oxidase** (Complex IV) is the terminal enzyme in the **electron transport chain**, responsible for the reduction of oxygen to water. - Its main role is in cellular respiration, and it is not directly involved in drug monooxygenation or detoxification.
Question 2: Which of the following is the platinum-based chemotherapeutic agent used as first-line treatment for ovarian carcinoma?
- A. Cyclophosphamide
- B. Methotrexate
- C. Cisplatin (Correct Answer)
- D. Dacarbazine
Explanation: ***Cisplatin*** - **Cisplatin** is a platinum-based chemotherapy drug that forms **DNA cross-links**, inhibiting DNA synthesis and leading to the death of rapidly dividing cells, making it highly effective against **ovarian carcinoma**. - It is a cornerstone of chemotherapy regimens for ovarian cancer, often used in combination with other agents such as paclitaxel. *Methotrexate* - **Methotrexate** is an **antimetabolite** that inhibits dihydrofolate reductase, thereby interfering with DNA synthesis. - While it is used in various cancers like leukemia, lymphoma, and some solid tumors (e.g., breast cancer, gestational trophoblastic disease), it is **not a primary recommended drug for ovarian carcinoma**. *Cyclophosphamide* - **Cyclophosphamide** is an **alkylating agent** that causes DNA damage, leading to cell death. - It is used in many cancers, including lymphoma, breast cancer, and some leukemias, but it is **not a first-line or primary agent for ovarian carcinoma** in contemporary treatment guidelines. *Dacarbazine* - **Dacarbazine** is an **alkylating agent** primarily used in the treatment of **malignant melanoma** and Hodgkin lymphoma. - It is **not indicated for the treatment of ovarian carcinoma**.
Question 3: Match the following drugs in Column A with their contraindications in Column B. | Column A | Column B | | :-- | :-- | | 1. Morphine | 1. QT prolongation | | 2. Amiodarone | 2. Thromboembolism | | 3. Vigabatrin | 3. Pregnancy | | 4. Estrogen preparations | 4. Head injury |
- A. A-1, B-3, C-2, D-4
- B. A-4, B-1, C-3, D-2 (Correct Answer)
- C. A-3, B-2, C-4, D-1
- D. A-2, B-4, C-1, D-3
Explanation: ***A-4, B-1, C-3, D-2*** - **Morphine** is contraindicated in **head injury** as it can increase intracranial pressure and mask neurological symptoms. - **Amiodarone** is contraindicated in patients with **QT prolongation** due to its risk of inducing more severe arrhythmias like Torsades de Pointes. - **Vigabatrin** is contraindicated during **pregnancy** due to its potential for teratogenicity and adverse effects on fetal development. - **Estrogen preparations** are contraindicated in patients with a history of **thromboembolism** due to their increased risk of blood clot formation. *A-1, B-3, C-2, D-4* - This option incorrectly matches **Morphine** with QT prolongation and **Estrogen preparations** with head injury, which are not their primary contraindications. - It also incorrectly links **Vigabatrin** with thromboembolism and **Amiodarone** with pregnancy. *A-3, B-2, C-4, D-1* - This choice incorrectly associates **Morphine** with pregnancy and **Vigabatrin** with head injury, which are not the most critical or direct contraindications. - It also misaligns **Amiodarone** with thromboembolism and **Estrogen preparations** with QT prolongation. *A-2, B-4, C-1, D-3* - This option incorrectly matches **Morphine** with thromboembolism and **Amiodarone** with head injury, which are not their most significant contraindications. - It also incorrectly links **Vigabatrin** with QT prolongation and **Estrogen preparations** with pregnancy.
Question 4: Which of the following cytochromes is involved in monooxygenase mediated detoxification of drugs?
- A. Cytochrome b5
- B. Cytochrome P450 (Correct Answer)
- C. Cytochrome c
- D. NADPH-cytochrome P450 reductase
Explanation: ***Cyt P 450*** - **Cytochrome P450** enzymes are a superfamily of **monooxygenases** that play a critical role in the metabolism and detoxification of a wide variety of endogenous and exogenous substances, including drugs. - They facilitate phase I reactions (e.g., **oxidation**, reduction, hydrolysis), which typically introduce or expose functional groups to make compounds more polar and easier to excrete. *Cytochrome b5* - **Cytochrome b5** is involved in various metabolic reactions, including **fatty acid desaturation** and cholesterol biosynthesis, and can sometimes interact with P450 systems but is not the primary monooxygenase for drug detoxification. - It also participates in the reduction of methemoglobin and can act as an electron donor, but its role in drug detoxification is secondary and accessory to P450. *Cytochrome c* - **Cytochrome c** is a key component of the **electron transport chain** in mitochondria, primarily involved in cellular respiration and ATP production. - It has a crucial role in **apoptosis** when released into the cytosol, but it is not directly involved in drug monooxygenase detoxification. *NADPH-cytochrome P450 reductase* - **NADPH-cytochrome P450 reductase** is an enzyme that transfers electrons from NADPH to **cytochrome P450 enzymes**, enabling their monooxygenase activity. - While essential for P450 function, it is the **reductase** (electron donor) and not the monooxygenase enzyme itself, which is Cytochrome P450.
Question 5: A lady gets pregnant even though she was on contraceptive pills. She is suspected to have consumed
- A. Ciprofloxacin
- B. Rifampicin (Correct Answer)
- C. Streptomycin
- D. None of these
Explanation: ***Rifampicin*** - **Rifampicin** is a potent inducer of **hepatic microsomal enzymes** (cytochrome P450 enzymes), particularly CYP3A4. - This enzyme induction leads to increased metabolism and thus decreased effectiveness of **oral contraceptive pills**, raising the risk of unintended pregnancy. *Ciprofloxacin* - **Ciprofloxacin** is a **quinolone antibiotic** that primarily works by inhibiting bacterial DNA gyrase and topoisomerase IV. - It does not significantly induce hepatic enzymes or interfere with the efficacy of **oral contraceptive pills**. *Streptomycin* - **Streptomycin** is an **aminoglycoside antibiotic** that inhibits bacterial protein synthesis. - It is not known to have a significant drug interaction with **oral contraceptive pills** that would lead to contraceptive failure. *None of these* - This option is incorrect because **Rifampicin** is well-documented to reduce the effectiveness of **oral contraceptive pills**.
Question 6: Which of the following combinations can result in severe toxicity due to inhibition of cytochrome P450 enzymes?
- A. Amiodarone + Atorvastatin
- B. Carbamazepine + Atorvastatin
- C. Atorvastatin + Itraconazole (Correct Answer)
- D. Phenytoin + Atorvastatin
Explanation: ***Atorvastatin + Itraconazole*** - **Itraconazole** is a potent inhibitor of **CYP3A4**, the primary enzyme responsible for atorvastatin's metabolism. - Co-administration leads to significantly increased **atorvastatin plasma concentrations**, raising the risk of severe side effects like **rhabdomyolysis** and **hepatotoxicity**. *Amiodarone + Atorvastatin* - **Amiodarone** is a moderate **CYP3A4 inhibitor** and can increase atorvastatin levels, but the inhibition is **less potent** than itraconazole. - While this combination does carry a risk and requires dose adjustment, the interaction is **less severe** compared to the potent inhibition seen with itraconazole. - The direct CYP inhibition leading to severe atorvastatin toxicity is less pronounced than with itraconazole. *Carbamazepine + Atorvastatin* - **Carbamazepine** is a potent **CYP3A4 inducer**, meaning it would increase the metabolism of atorvastatin, potentially *decreasing* its efficacy rather than causing toxicity through inhibition. - This interaction would typically lead to subtherapeutic atorvastatin levels, rather than severe toxicity. *Phenytoin + Atorvastatin* - **Phenytoin** is also a potent **CYP3A4 inducer**, similar to carbamazepine. - Concurrent use would likely lead to enhanced metabolism and **reduced efficacy of atorvastatin**, not increased toxicity due to enzyme inhibition.
Question 7: Centrilobular necrosis of the liver may be seen with?
- A. Arsenic
- B. Ethanol
- C. CCl4 (Correct Answer)
- D. Phosphorus
Explanation: ***CCl4*** - **Carbon tetrachloride (CCl4)** is the **classic and prototypical** hepatotoxin that causes **centrilobular (zone 3) necrosis**. - The **centrilobular zone (zone 3)** is particularly vulnerable due to its high concentration of **cytochrome P450 enzymes**, which metabolize CCl4 into **toxic free radicals (trichloromethyl radicals)**. - This is the **most characteristic** cause of centrilobular necrosis in toxicology and is the preferred answer for exam purposes. *Ethanol* - **Ethanol** can also cause **centrilobular necrosis** in **alcoholic hepatitis**, as zone 3 is most susceptible to hypoxic injury and oxidative stress. - However, alcoholic liver disease presents with a **spectrum of changes** including steatosis (earliest), hepatitis with ballooning degeneration and Mallory-Denk bodies, and eventual cirrhosis. - While centrilobular necrosis occurs in alcoholic hepatitis, **CCl4 remains the prototype** for pure centrilobular necrosis in exam contexts. *Phosphorus* - **Elemental phosphorus** toxicity causes **periportal (zone 1) necrosis**, which is the opposite pattern from centrilobular necrosis. - It also causes widespread fatty change and hemorrhagic necrosis within the liver. *Arsenic* - **Arsenic poisoning** causes **diffuse/generalized hepatocellular necrosis** and cholestasis, rather than the specific centrilobular pattern. - Chronic exposure is associated with non-cirrhotic portal fibrosis and portal hypertension.
Question 8: Chemical process involved in conversion of progesterone to glucocorticoids is
- A. Methylation
- B. Hydroxylation (Correct Answer)
- C. Carboxylation
- D. None of the options
Explanation: ***Hydroxylation*** - The conversion of progesterone to glucocorticoids involves several enzymatic steps, with **hydroxylation reactions** being critical for adding hydroxyl groups at specific carbon positions (e.g., C-17, C-21, C-11). - These hydroxylation steps are catalyzed by various **cytochrome P450 enzymes** (e.g., 17α-hydroxylase, 21-hydroxylase, 11β-hydroxylase) within the adrenal cortex, leading to the formation of active glucocorticoids like **cortisol**. *Methylation* - **Methylation** involves the addition of a methyl group (-CH₃) to a molecule, a process more commonly associated with modifying DNA, proteins, or certain neurotransmitters. - While methylation is a vital biological process, it is not the primary chemical reaction involved in the **steroidogenesis pathway** converting progesterone to glucocorticoids. *Carboxylation* - **Carboxylation** is the addition of a carboxyl group (-COOH) to a molecule, a reaction crucial in processes like photosynthesis (carbon fixation) or the synthesis of certain proteins (e.g., clotting factors). - This chemical modification is not directly involved in the series of transformations that convert progesterone into **glucocorticoids**. *None of the options* - This option is incorrect because **hydroxylation** is indeed a fundamental chemical process in the conversion of progesterone to glucocorticoids.
Question 9: Drugs used for Prophylaxis of migraine include the following except?
- A. Valproate
- B. Sumatriptan (Correct Answer)
- C. TCAs
- D. Propranolol
Explanation: ***Sumatriptan*** - **Sumatriptan** is a **triptan** drug class medication (5-HT1B/1D receptor agonist) used for the **acute treatment** of migraine attacks, not for prophylaxis. - It works by causing cranial vasoconstriction and inhibiting neuropeptide release, thereby aborting an active migraine attack. - Triptans are contraindicated in patients with coronary artery disease due to their vasoconstrictive effects. *Valproate* - **Valproate** (sodium valproate/divalproex) is an established **first-line agent for migraine prophylaxis**. - It exerts antimigraine effects through modulation of GABAergic transmission, voltage-gated sodium channels, and possibly NMDA receptor inhibition. - Effective dose for prophylaxis is typically 500-1000 mg/day in divided doses. *Propranolol* - **Propranolol**, a non-selective **beta-blocker**, is one of the most commonly used **first-line prophylactic agents** for migraine. - It reduces migraine frequency through multiple mechanisms including inhibition of norepinephrine, reduction of cortical spreading depression, and stabilization of vascular tone. - Typical prophylactic dose is 80-240 mg/day in divided doses. *TCAs* - **Tricyclic antidepressants (TCAs)**, particularly **amitriptyline**, are highly effective **first-line prophylactic agents** for migraine. - They work through modulation of serotonin and norepinephrine reuptake, as well as effects on ion channels and pain pathways. - Amitriptyline is typically used at doses of 25-150 mg at bedtime for migraine prophylaxis.
Question 10: Testing of HLA-B' 5701 is recommended prior to initiation of which antiretroviral agent?
- A. Atazanavir
- B. Nelfinavir
- C. Raltegravir
- D. Abacavir (Correct Answer)
Explanation: The correct answer is **Abacavir (Option D)**. **1. Why Abacavir is Correct:** Abacavir is a Nucleoside Reverse Transcriptase Inhibitor (NRTI) associated with a severe, potentially life-threatening **Hypersensitivity Reaction (HSR)** [1]. This reaction is strongly linked to the presence of the **HLA-B*57:01** allele. In individuals carrying this allele, abacavir binds to the HLA-B*57:01 protein, altering the shape of the antigen-binding cleft [1]. This causes the immune system to recognize self-peptides as foreign, triggering a massive T-cell response. Screening for this allele is now a standard of care; if a patient tests positive, abacavir is strictly contraindicated [1]. **2. Why Other Options are Incorrect:** * **Atazanavir (A):** A Protease Inhibitor (PI) known for causing unconjugated hyperbilirubinemia (jaundice) by inhibiting the UGT1A1 enzyme, but it is not linked to HLA-B*57:01 [1]. * **Nelfinavir (B):** An older PI primarily associated with gastrointestinal side effects (diarrhea). No specific HLA screening is required. * **Raltegravir (C):** An Integrase Strand Transfer Inhibitor (INSTI). While it can rarely cause Stevens-Johnson Syndrome (SJS), there is no routine pharmacogenetic screening recommended prior to its use. **3. High-Yield Clinical Pearls for NEET-PG:** * **Abacavir HSR Symptoms:** Fever, rash, GI distress, and respiratory symptoms. **Re-challenge** after a suspected reaction is **fatal**. * **Other High-Yield HLA Associations:** * **HLA-B*15:02:** Carbamazepine-induced SJS/TEN (specifically in Asian populations). * **HLA-B*58:01:** Allopurinol-induced severe cutaneous adverse reactions (SCAR). * **Mnemonic:** "A-B-C" — **A**bacavir **B**inds **C**left of HLA-B*57:01.
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