Which is the main intracellular antioxidant that protects red cells from oxidative damage?
Answer: Reduced glutathione
Reduced glutathione (GSH) neutralises hydrogen peroxide via glutathione peroxidase. It is kept reduced by NADPH from the pentose phosphate pathway (G6PD). In G6PD deficiency, glutathione cannot be regenerated, so oxidant drugs cause haemolysis.
G6PD deficiency: haemolysis with primaquine, dapsone, fava beans
Film: Heinz bodies, bite cells
Remember G6PD powers the shield (glutathione).
Why the other options are wrong
Vitamin A (retinol) A minor antioxidant compared with glutathione.
Haemoglobin Carries oxygen and is a target of oxidation.
Serum albumin A plasma antioxidant, not the main intracellular one.
Vitamin E (tocopherol) Protects membrane lipids, but glutathione is the main intracellular reducing agent.
Question 2Medium
After a week of starvation, what becomes a major energy source for the brain?
Answer: Ketone bodies
Early in fasting, the brain uses glucose from glycogen and then gluconeogenesis. After several days, ketone bodies (acetoacetate, β-hydroxybutyrate) made by the liver from fatty acids cross the blood–brain barrier and supply up to two-thirds of the brain's energy, sparing muscle protein. Fatty acids cannot cross the barrier.
Remember Brain switches to ketones to save the muscles.
Why the other options are wrong
Fatty acids directly Cannot cross the blood–brain barrier.
Glycogen from the liver Used up within about 24 hours.
Dietary glucose No intake in starvation.
Amino acids directly Used for gluconeogenesis, not directly by the brain.
Question 3Medium
Which is the most important buffer in the extracellular fluid?
Answer: Bicarbonate buffer
The bicarbonate system is the main ECF buffer because both parts are regulated: CO₂ by the lungs and bicarbonate by the kidneys. Haemoglobin is the main buffer inside red cells; proteins and phosphate buffer inside cells; phosphate and ammonia buffer urine, allowing acid excretion.
Body buffers
ECF: bicarbonate
RBC: haemoglobin; cells: proteins, phosphate
Urine: phosphate, ammonia
Remember Bicarbonate: lungs and kidneys both control it.
Why the other options are wrong
Haemoglobin Main red cell buffer.
Phosphate Main urinary and intracellular buffer.
Plasma proteins Intracellular and plasma, but less important.
Ammonia Urinary buffer.
Question 4Medium
Which enzyme converts superoxide radicals into hydrogen peroxide?
Answer: Superoxide dismutase
Defence against reactive oxygen species: superoxide dismutase (O₂⁻ → H₂O₂), catalase and glutathione peroxidase (H₂O₂ → H₂O). Non-enzymatic antioxidants: vitamins C and E, β-carotene, glutathione. Neutrophils deliberately make superoxide (NADPH oxidase) and hypochlorite (myeloperoxidase) to kill microbes. SOD1 mutations cause some familial ALS.
A man in septic shock after a bowel perforation is changed from noradrenaline to an adrenaline infusion. Over the next few hours his capillary refill and urine output improve, and his abdomen is unchanged on examination, yet lactate rises from 2.1 to 5.0 mmol/L and glucose rises to 14 mmol/L (250 mg/dL). A repeat CT shows no new collection or ischaemic bowel. Which of the following best explains the rising lactate?
Answer: β2-driven aerobic glycolysis in muscle
Adrenaline stimulates β2 receptors on skeletal muscle, increasing glycogenolysis and glycolysis and activating the Na⁺/K⁺-ATPase. Pyruvate is then produced faster than it can enter mitochondria, so lactate rises even though oxygen delivery is adequate (type B hyperlactataemia). Hepatic glycogenolysis also raises glucose. Improving perfusion markers suggest this is a drug effect, not new tissue hypoxia.
Adrenaline and lactate
β2 in muscle drives glycolysis
Lactate rises without hypoxia
Also hyperglycaemia
Called type B hyperlactataemia
Remember Adrenaline raises lactate by itself.
Exam trap Do not escalate fluids or surgery on lactate alone in a patient on adrenaline; look at perfusion.
Why the other options are wrong
New ischaemia of the bowel Perfusion markers are improving, against new ischaemia.
Lactate in the infusion fluid Standard infusions are not a meaningful lactate source.
Reduced liver blood flow from α1 Adrenaline does not reduce liver flow enough to explain this.
Mitochondrial poisoning by adrenaline Adrenaline does not poison mitochondria.
Question 6Hard
Villagers who have drunk from the same tube well for years develop raindrop pigmentation, thick palmar keratoses and a painful sensorimotor neuropathy. Water testing confirms arsenic. Which biochemical action of arsenic best explains its toxicity?
Answer: Binds lipoic acid in pyruvate dehydrogenase
Trivalent arsenic binds tightly to paired sulfhydryl groups, especially the dithiol of lipoic acid, a cofactor of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Blocking these enzymes cuts acetyl-CoA formation and the Krebs cycle, so nerves and other active tissues are starved of ATP, and lactate rises. Pentavalent arsenate can also replace phosphate and uncouple ATP formation, but this is a lesser effect. Chronic exposure also causes skin, lung and bladder cancers.
Arsenic
Binds sulfhydryl groups
Blocks lipoic acid enzymes (PDH, alpha-KGDH)
Skin raindrop pigmentation, keratoses
Cancers: skin, lung, bladder
Remember Arsenic poisons lipoic acid; no acetyl-CoA, no energy.
Exam trap Do not confuse arsenic's skin and nail changes with lead lines; lead gives anaemia and wrist drop.
Why the other options are wrong
Inhibits ALA dehydratase in haem synthesis This is lead poisoning.
Blocks cytochrome c oxidase Cyanide and hydrogen sulphide act here.
Inhibits acetylcholinesterase Organophosphates and carbamates act here.
Uncouples oxidative phosphorylation Classic for dinitrophenol and aspirin overdose; only a minor action of arsenate.
Question 7Medium
A woman in preterm labour at 33 weeks has an amniotic fluid sample taken, and the lecithin–sphingomyelin ratio is reported as 2.5. What does this ratio assess?
Answer: Fetal lung surfactant maturity
Type II pneumocytes secrete surfactant, rich in lecithin (dipalmitoyl phosphatidylcholine), into fetal lung fluid, which passes into the amniotic fluid. Sphingomyelin stays fairly constant, so a rising lecithin-to-sphingomyelin ratio reflects increasing surfactant production. A ratio of 2 or more indicates that respiratory distress syndrome is unlikely. Neural tube defects are assessed by AFP and acetylcholinesterase instead.
L/S ratio
Lecithin from type II pneumocytes
Sphingomyelin constant
Ratio 2 or more: mature lungs
Low ratio: risk of RDS
Remember L/S over 2: lungs are ready.
Exam trap In diabetic pregnancy a mature-looking ratio may still be followed by RDS.
Why the other options are wrong
Fetal neural tube integrity Assessed by AFP and acetylcholinesterase.
Fetal renal concentrating ability Not tested by this ratio.
Fetal liver bilirubin clearance Bilirubin in fluid is assessed by spectrophotometry.
Fetal chromosomal make-up Needs karyotype or genetic testing.
Question 8Hard
The corpus luteum secretes up to about 40 mg of progesterone a day but makes little cholesterol itself. How do luteal cells mainly obtain the cholesterol they need?
Answer: LDL receptor–mediated endocytosis
Steroid-producing cells, including the corpus luteum, placenta and adrenal cortex, take up most of their cholesterol from circulating LDL. LDL binds LDL receptors on the cell surface, is internalised in clathrin-coated pits and broken down in lysosomes, releasing free cholesterol. LH and hCG increase LDL receptor expression, and the corpus luteum's rich blood supply delivers large amounts of LDL. HDL uptake through SR-BI also contributes.
Cholesterol for progesterone
Main source: LDL
Uptake by LDL receptor
LH/hCG increase LDL receptors
Lysosomes release free cholesterol
Remember Luteal cells buy cholesterol from LDL.
Exam trap The placenta also relies on maternal LDL, since it cannot make enough cholesterol.
Why the other options are wrong
De novo synthesis from acetate A minor source in luteal cells.
Diffusion of free plasma cholesterol Free cholesterol is carried on lipoproteins, not dissolved.
Uptake of chylomicrons Chylomicrons deliver dietary fat to the liver and tissues, not steroid cells.
Breakdown of membrane phospholipids Not a source of cholesterol.
Question 9Hard
A 46,XY infant has female external genitalia and a salt-wasting crisis. All adrenal and gonadal steroids are very low, and imaging shows enlarged adrenals filled with lipid. Which step, the rate-limiting one in steroid synthesis, is defective?
Answer: Cholesterol entry into mitochondria
The rate-limiting step in all steroid synthesis is the transfer of cholesterol from the outer to the inner mitochondrial membrane by the steroidogenic acute regulatory (StAR) protein, followed by side-chain cleavage to pregnenolone. LH in Leydig and theca cells and ACTH in the adrenal both act mainly by increasing StAR activity. In congenital lipoid adrenal hyperplasia, StAR fails, so no steroids are made and cholesterol accumulates in the cells. A 46,XY infant then lacks testosterone and appears female.
Rate-limiting steroid step
StAR moves cholesterol into mitochondria
Side-chain cleavage to pregnenolone
LH and ACTH act here
Defect: lipoid adrenal hyperplasia
Remember No StAR, no steroids at all.
Exam trap Enzymes later in the pathway affect only some steroids; this defect removes them all.
Why the other options are wrong
Pregnenolone to progesterone 3β-HSD step; not rate-limiting.
Androstenedione to testosterone 17β-HSD step; not rate-limiting.
Testosterone to dihydrotestosterone 5α-reductase; would not affect cortisol.
Acetyl CoA to cholesterol Cholesterol is supplied from LDL; not the defect.
Question 10Hard
During each uterine contraction in labour, myometrial cytosolic calcium rises and ADP accumulates, and the TCA cycle speeds up to supply NADH. Which TCA enzyme is the main rate-limiting step activated by these signals?
Answer: Isocitrate dehydrogenase
Isocitrate dehydrogenase, which converts isocitrate to alpha-ketoglutarate with production of NADH and CO2, is the main rate-limiting enzyme of the TCA cycle. It is activated by ADP and calcium, signals of muscle activity and low energy charge, and inhibited by ATP and NADH. Calcium also activates pyruvate dehydrogenase phosphatase and alpha-ketoglutarate dehydrogenase, linking contraction to oxidative metabolism.
Isocitrate dehydrogenase
Main rate-limiting TCA enzyme
Activated by ADP and Ca2+
Inhibited by ATP and NADH
Makes NADH and CO2
Remember Contraction signals open the TCA cycle at isocitrate DH.
Exam trap Alpha-ketoglutarate dehydrogenase is also calcium-sensitive, but isocitrate DH is the classic rate-limiting step.
Why the other options are wrong
Citrate synthase Citrate synthase is regulated by substrate supply and inhibited by citrate and ATP, but is not the main calcium-activated step.
Succinyl-CoA synthetase Succinyl-CoA synthetase makes GTP and is not rate-limiting.
Fumarase Fumarase is a reversible, non-regulatory step.
Aconitase Aconitase is not a major regulatory step.
Question 11Hard
In late pregnancy, high free fatty acids from placental lactogen-driven lipolysis are oxidised by maternal muscle, and its glucose use falls. Which molecule, exported from mitochondria to the cytosol, directly inhibits phosphofructokinase-1 in this setting?
Answer: Citrate
Fatty acid oxidation produces acetyl-CoA, which combines with oxaloacetate to form citrate. Citrate moves into the cytosol and allosterically inhibits PFK-1, slowing glycolysis, while acetyl-CoA and NADH inhibit pyruvate dehydrogenase. This glucose–fatty acid (Randle) cycle reduces muscle glucose uptake and use, contributing to the insulin resistance of late pregnancy that diverts glucose to the fetus.
Randle cycle
Fat oxidation: citrate rises
Citrate inhibits PFK-1
Acetyl-CoA inhibits PDH
Less glucose use by muscle
Remember Burning fat slows glycolysis through citrate.
Exam trap Malonyl-CoA works the other way, stopping fat oxidation when glucose is plentiful.
Malonyl-CoA Malonyl-CoA inhibits carnitine palmitoyltransferase I, not PFK-1.
Question 12Hard
Insulin does not cross the placenta in useful amounts, yet malformations are increased when maternal diabetes is poorly controlled in the first 8 weeks. What is the main mechanism of this embryopathy?
Answer: Hyperglycaemic oxidative stress
Glucose crosses the placenta freely, so the embryo shares the mother's hyperglycaemia. Excess glucose increases mitochondrial production of reactive oxygen species and alters expression of developmental genes, such as Pax3 in the neural tube, leading to apoptosis of key cell populations. The embryonic pancreas does not make insulin until later in the first trimester, so fetal hyperinsulinaemia explains macrosomia, not early malformations.
How diabetes deforms
Glucose crosses freely
Reactive oxygen species in embryo
Altered genes, apoptosis
Fetal insulin later: macrosomia
Remember Early sugar deforms; later insulin enlarges.
Exam trap Fetal hyperinsulinaemia causes macrosomia and neonatal hypoglycaemia, not structural defects.
Why the other options are wrong
Fetal hyperinsulinaemia in week 4 Starts later and causes macrosomia, not malformations.
Lack of maternal ketone bodies Ketones are raised, not reduced, in poor control.
Fetal hypoglycaemic episodes The embryo is hyperglycaemic, not hypoglycaemic.
Insulin crossing the placenta Insulin does not cross the placenta.
