Page 4 of 4
BI12.1-3 | Xenobiotic, oxidative stress and antioxidants — Gate Quiz
Click any question card to reveal the correct answer.
Phase I drug metabolism reactions primarily involve which type of chemical reaction?
Correct! Phase I reactions (oxidation, reduction, hydrolysis) are catalyzed primarily by cytochrome P450 (CYP) enzymes in the smooth ER of the liver, introducing or exposing functional groups.
Drug metabolism phases: Phase I (CYP enzymes): oxidation (most common), reduction, hydrolysis. Adds/exposes polar groups. May activate pro-drugs or create reactive metabolites. Phase II (transferases): conjugation with glucuronate (UGT), sulfate (SULT), glutathione (GST), or acetyl (NAT). Generally increases water solubility for excretion.
Incorrect. Phase I reactions = oxidation/reduction/hydrolysis by CYP enzymes. Phase II = conjugation reactions.
Click to reveal answer
Rifampicin (an anti-TB drug) is a potent inducer of cytochrome P450 (CYP3A4) enzymes. A patient taking both rifampicin and the oral contraceptive pill (OCP) may experience:
Correct! Rifampicin induces CYP3A4, increasing metabolism (breakdown) of OCP hormones (oestrogen and progestogen), reducing their plasma levels and contraceptive efficacy — risk of unintended pregnancy.
CYP450 inducers (CRAP GPS): Carbamazepine, Rifampicin, Alcohol (chronic), Phenytoin, Griseofulvin, Phenobarbitone, St Johns Wort. All decrease efficacy of co-administered drugs. Inhibitors (SICKFACE): increase drug levels (toxicity risk). Important for warfarin, OCP, cyclosporin, antiretrovirals, statins.
Incorrect. Enzyme induction by rifampicin accelerates OCP metabolism, reducing contraceptive efficacy.
Click to reveal answer
Paracetamol (acetaminophen) overdose causes acute liver failure. The toxic mechanism involves:
Correct! Paracetamol is converted by CYP2E1/CYP3A4 to NAPQI (N-acetyl-p-benzoquinone imine). At therapeutic doses, NAPQI is detoxified by glutathione (GSH). In overdose, GSH is depleted, NAPQI accumulates and causes hepatocellular necrosis.
Treatment of paracetamol overdose: N-acetylcysteine (NAC) replenishes GSH precursor (cysteine), preventing NAPQI accumulation. Must be given within 8-10 hours for maximum benefit. Alcohol (CYP2E1 inducer) and fasting (depleted GSH) increase paracetamol hepatotoxicity risk. Hepatotoxic dose: usually greater than 150 mg/kg or 7.5-10 g in adults.
Incorrect. Paracetamol hepatotoxicity = GSH depletion + NAPQI accumulation.
Click to reveal answer
A free radical is defined as:
Correct! A free radical is any atom or molecule with one or more unpaired electrons in its outer orbital. The unpaired electron makes it highly reactive. Examples: superoxide (O2-), hydroxyl radical (OH-), NO.
Important free radicals (reactive oxygen species): Superoxide (O2- from ETC), Hydroxyl radical (OH- most reactive, from Fenton reaction: Fe2+ + H2O2), Nitric oxide (NO, vasodilator). Reactive nitrogen species: peroxynitrite (ONOO-). ROS cause: lipid peroxidation, protein oxidation, DNA damage (strand breaks, base modifications).
Incorrect. Free radicals are defined by having one or more unpaired electrons, making them highly reactive.
Click to reveal answer
A patient with G6PD deficiency develops haemolytic anaemia after taking primaquine (anti-malarial). The mechanism is:
Correct! G6PD is required for the HMP shunt to produce NADPH. NADPH is required for glutathione reductase (GSH regeneration). Without GSH, RBCs cannot neutralize oxidative stress from primaquine, causing Heinz body formation and haemolysis.
G6PD deficiency: X-linked recessive, most common enzyme defect. NADPH from HMP shunt keeps glutathione reduced (GSH). Oxidative drugs (primaquine, dapsone, nitrofurantoin), infections, fava beans trigger haemolysis. Heinz bodies = denatured haemoglobin precipitates. Treatment: avoid triggers, supportive care.
Incorrect. G6PD deficiency impairs NADPH production, reducing GSH, leaving RBCs vulnerable to oxidative damage.
Click to reveal answer
Superoxide radicals generated by the mitochondrial ETC are converted to hydrogen peroxide by superoxide dismutase. Hydrogen peroxide is then neutralized by:
Correct! H2O2 is neutralized by: (1) Catalase in peroxisomes: 2H2O2 → 2H2O + O2. (2) Glutathione peroxidase (GPx): H2O2 + 2GSH → GSSG + 2H2O. GSSG is regenerated to GSH by glutathione reductase using NADPH.
Antioxidant cascade: O2- (superoxide) → (SOD) → H2O2 → (Catalase or GPx) → H2O. NADPH (from HMP shunt, via G6PD) regenerates GSH. G6PD deficiency impairs this entire cascade. Vitamin E quenches lipid peroxyl radicals directly in membranes.
Incorrect. H2O2 is neutralized by catalase or glutathione peroxidase (not SOD again).
Click to reveal answer
Glucuronidation is the most common Phase II conjugation reaction. The activated donor molecule used in glucuronidation is:
Correct! UDP-glucuronate (UDPGA) is the activated glucuronyl donor. Glucuronyl transferases (UGTs) transfer glucuronate to drugs, bilirubin, steroids, and other compounds to increase water solubility.
Phase II conjugation donors: Glucuronidation = UDP-glucuronate (UDPGA, most important). Sulfation = PAPS (phosphoadenosine-phosphosulfate). Methylation = SAM (S-adenosylmethionine). Acetylation = Acetyl-CoA. Glutathione conjugation = GSH. Glycine conjugation = Glycine. Neonatal jaundice: UGT1A1 immature, cannot conjugate bilirubin.
Incorrect. UDP-glucuronate (UDPGA) is the glucuronyl donor in glucuronidation reactions.
Click to reveal answer
Oral propranolol is extensively metabolized by the liver before reaching systemic circulation. This phenomenon is called:
Correct! The first pass effect (first pass metabolism) occurs when a drug absorbed from the gut is metabolized by the liver (via portal circulation) before reaching systemic circulation, reducing bioavailability.
Drugs with high first pass effect require: higher oral doses vs. IV doses (propranolol, lidocaine, morphine, nitroglycerin, aspirin). Sublingual, buccal, transdermal, or IV routes bypass first pass. Liver disease (cirrhosis) increases bioavailability of high first-pass drugs. Useful for prodrugs like enalapril (converted to active enalaprilat in liver).
Incorrect. Extensive hepatic metabolism of absorbed drug before reaching systemic circulation is the first pass effect.
Click to reveal answer
Oxidative stress contributes to the pathogenesis of atherosclerosis by:
Correct! Oxidative stress: (1) reduces NO bioavailability (NO is quenched by superoxide to form peroxynitrite), impairing endothelial function; (2) oxidizes LDL to oxLDL, which is taken up by macrophages via scavenger receptors (not downregulated), forming foam cells — the hallmark of early atherosclerosis.
Oxidative stress in atherosclerosis: oxLDL is more atherogenic than native LDL. Foam cells loaded with cholesterol form fatty streaks. Antioxidants (Vitamin E, polyphenols) reduce LDL oxidation in vitro but clinical trial evidence for atherosclerosis prevention is inconsistent. Statins have antioxidant effects beyond LDL lowering.
Incorrect. Oxidative stress reduces NO and oxidises LDL to oxLDL, both key steps in atherosclerosis.
Click to reveal answer
Ketoconazole (antifungal) inhibits CYP3A4. A patient taking both ketoconazole and simvastatin (a statin metabolized by CYP3A4) may experience:
Correct! Ketoconazole inhibits CYP3A4, reducing simvastatin metabolism, leading to elevated simvastatin plasma levels and increased risk of myopathy (muscle damage, rhabdomyolysis).
Important CYP3A4 inhibitors (SICKFACE mnemonic): Sodium valproate, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Amiodarone, Chloramphenicol, Erythromycin. CYP inhibition increases levels of co-administered drugs, risking toxicity. Simvastatin CYP3A4 interactions: avoid with azole antifungals, macrolide antibiotics — use pravastatin (not CYP3A4) instead.
Incorrect. CYP inhibition by ketoconazole increases simvastatin levels, risking myopathy.
Click to reveal answer