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Detoxification & Xenobiotics

Tier 2 · #18 of 33 · high yield · topic 4.8 — every high-yield fact from the book chapter, exam-ready.

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  1. Front
    What is a xenobiotic ?
    Back
    A compound foreign to the body (drug, carcinogen, insecticide, pollutant) with no metabolic value that does not enter any typical metabolic pathway.
  2. Front
    Why do xenobiotics accumulate in the body rather than being excreted directly?
    Back
    They are lipophilic , so they partition into membranes and adipose tissue instead of dissolving in plasma or urine.
  3. Front
    Why is the liver the principal site of detoxification?
    Back
    It receives the entire portal blood supply (everything absorbed from the gut passes through it first) and hepatocytes express the detox enzymes at high concentration.
  4. Front
    In one phrase, what does Phase I detoxification do to a xenobiotic ?
    Back
    Converts a lipophilic xenobiotic into a more polar intermediate (chiefly by hydroxylation ).
  5. Front
    In one phrase, what does Phase II detoxification do to a xenobiotic ?
    Back
    Attaches a large, charged molecule ( conjugation ) to yield a water-soluble product excreted in urine or bile.
  6. Front
    What enzyme family carries out Phase I reactions?
    Back
    Cytochrome P450 (CYP) enzymes .
  7. Front
    What is the chief chemical reaction performed by cytochrome P450 in Phase I ?
    Back
    Hydroxylation (insertion of an —OH group).
  8. Front
    Cytochrome P450 enzymes belong to what mechanistic class of enzyme?
    Back
    Monooxygenases — they insert one atom of O₂ into the substrate and reduce the other to water.
  9. Front
    Which enzyme donates the electrons used by cytochrome P450 in Phase I ?
    Back
    Cytochrome P450 reductase .
  10. Front
    What reactive side product is generated by the cytochrome P450 reaction, contributing to oxidative stress?
    Back
    The superoxide radical (O₂⁻) .
  11. Front
    In which subcellular membrane are most CYP enzymes located in the liver?
    Back
    The smooth endoplasmic reticulum (the microsomal fraction ).
  12. Front
    Where (other than the smooth ER) are CYP enzymes found in the adrenal gland , and what do they do there?
    Back
    In mitochondria , where they handle steroid biosynthesis with much stricter substrate specificity.
  13. Front
    Which CYP isoform dominates human drug metabolism (metabolizes the largest number of drugs)?
    Back
    CYP3A4 .
  14. Front
    CYP3A4 accounts for roughly what percentage of CYP enzymes in hepatocytes ?
    Back
    About 60% .
  15. Front
    CYP3A4 accounts for roughly what percentage of CYP enzymes in enterocytes ?
    Back
    About 70% .
  16. Front
    When a drug INDUCES CYP3A4 , what happens to the plasma concentration of a co-administered CYP3A4 substrate?
    Back
    Its clearance is accelerated and its plasma concentration falls ( reduced effectiveness ).
  17. Front
    Through which nuclear receptor pathway does CYP induction signal travel?
    Back
    PXR (pregnane X receptor) heterodimerizing with RXR (retinoid X receptor) , binding the CYP3A4 promoter.
  18. Front
    Which herbal compound is the classic CYP3A4 INDUCER that can render anticoagulants, oral contraceptives, cyclosporine, digoxin, and statins ineffective?
    Back
    St. John's Wort .
  19. Front
    Which dietary substance is the classic IRREVERSIBLE inhibitor of intestinal CYP3A4 ?
    Back
    Grapefruit juice .
  20. Front
    Grapefruit juice inhibits CYP3A4 specifically in which cells?
    Back
    Enterocytes ( intestinal CYP3A4).
  21. Front
    Why does grapefruit-juice inhibition of CYP3A4 persist for 24–48 hours?
    Back
    Restoring activity requires de novo protein synthesis or enterocyte turnover (the inhibition is irreversible ).
  22. Front
    By inhibiting first-pass CYP3A4 , grapefruit juice can raise the blood level of statins by up to how much?
    Back
    Up to 15-fold (raising risk of myopathy and hepatotoxicity ).
  23. Front
    Phase I converts an active drug into what kind of product?
    Back
    An inactive metabolite (genuine detoxification ).
  24. Front
    Phase I converts a prodrug into what kind of product?
    Back
    The active drug (desirable activation ).
  25. Front
    Phase I converts a procarcinogen into what kind of product?
    Back
    A carcinogen (the opposite of detoxification ).
  26. Front
    Which procarcinogen (a polycyclic aromatic hydrocarbon from coal tar, diesel exhaust, and barbecued meat) is the textbook Phase-I activation example?
    Back
    Benzo[a]pyrene .
  27. Front
    Which specific CYP isoform converts benzo[a]pyrene to its reactive carcinogen, and what is that product?
    Back
    CYP1A1 converts it to benzo[a]pyrene diol epoxide .
  28. Front
    Which tumor suppressor gene is specifically targeted by benzo[a]pyrene diol epoxide DNA adducts?
    Back
    p53 .
  29. Front
    Which Phase II conjugation safely eliminates benzo[a]pyrene diol epoxide ?
    Back
    Glutathione (GSH) conjugation by glutathione S-transferase .
  30. Front
    CYP1A1 is induced by which substance, helping explain why chronic alcohol use increases cancer risk ?
    Back
    Ethanol .
  31. Front
    What is the most frequent Phase II conjugation reaction overall?
    Back
    Glucuronidation .
  32. Front
    Glucuronidation transfers glucuronic acid from which activated sugar donor?
    Back
    UDP-glucuronate .
  33. Front
    Glucuronidation of xenobiotics uses the same enzymes and donor as the conjugation of which endogenous compound?
    Back
    Bilirubin .
  34. Front
    Sulfotransferases transfer a sulfate group from which activated sulfate donor?
    Back
    PAPS (3′-phosphoadenosine-5′-phosphosulfate).
  35. Front
    Besides xenobiotics , PAPS is the sulfate donor for which endogenous molecules?
    Back
    Steroid hormones , glycosaminoglycans, glycolipids, and glycoproteins .
  36. Front
    Which familiar analgesic is named as a clinical Phase-II sulfation substrate?
    Back
    Acetaminophen (paracetamol) .
  37. Front
    Glutathione S-transferases act on xenobiotics bearing which kinds of reactive groups?
    Back
    Electrophilic groups such as epoxides, halides, or unsaturated carbonyls .
  38. Front
    After GSH conjugation, which two residues of glutathione are cleaved before the final acetylation step?
    Back
    Glutamate and glycine (leaving the cysteine conjugate ).
  39. Front
    The cysteine conjugate is acetylated by N-acetyltransferase using which cofactor to form a mercapturic acid derivative ?
    Back
    Acetyl-CoA .
  40. Front
    What is the rate-limiting factor for glutathione (GSH) synthesis?
    Back
    Availability of cysteine .
  41. Front
    What is the antidote for acetaminophen overdose , and how does it work?
    Back
    N-acetylcysteine (NAC) — it is hydrolyzed to cysteine , replenishing the limiting substrate for GSH synthesis.
  42. Front
    Besides being the acetaminophen antidote, NAC has what other clinical use?
    Back
    It is used as a mucolytic agent .
  43. Front
    What fraction of ingested ethanol is metabolized in the liver ?
    Back
    85–98% .
  44. Front
    What is the caloric value of ethanol per gram?
    Back
    7.1 kcal/g .
  45. Front
    Which enzyme is the MAJOR pathway for ethanol oxidation at moderate intake, and where is it located?
    Back
    Alcohol dehydrogenase (ADH) , in the cytoplasm .
  46. Front
    Why does ADH dominate ethanol oxidation at moderate drinking levels?
    Back
    It has a low Km (0.05–4 mM) , so it is saturated and active even at low ethanol concentrations.
  47. Front
    ADH converts ethanol to which product, with reduction of which cofactor?
    Back
    Acetaldehyde , with reduction of NAD⁺ to NADH .
  48. Front
    Which enzyme oxidizes acetaldehyde to acetate , and in which compartment?
    Back
    Aldehyde dehydrogenase (ALDH2) , in the mitochondria (also reducing NAD⁺ to NADH ).
  49. Front
    Disulfiram (Antabuse) works by inhibiting which enzyme?
    Back
    Aldehyde dehydrogenase (ALDH2) — causing toxic acetaldehyde to accumulate .
  50. Front
    The Microsomal Ethanol Oxidizing System (MEOS) uses which CYP enzyme?
    Back
    CYP2E1 .
  51. Front
    Why does MEOS (CYP2E1) only become significant at HIGH blood alcohol concentrations?
    Back
    It has a high Km (11 mM) , so it is only appreciably active when ethanol is high.
  52. Front
    By how much can chronic alcohol consumption increase MEOS (CYP2E1) activity, and by what mechanism?
    Back
    5–10-fold , because CYP2E1 is inducible .
  53. Front
    Unlike ADH , what damaging byproduct does the MEOS (CYP2E1) pathway generate?
    Back
    Free radicals / reactive oxygen species (ROS) , causing oxidative stress and lipid peroxidation.
  54. Front
    The two oxidative steps of ethanol metabolism flood the hepatocyte with which reduced cofactor?
    Back
    NADH (raising the NADH/NAD⁺ ratio).
  55. Front
    Why does high NADH from ethanol cause hypoglycemia ?
    Back
    Gluconeogenesis slows because oxaloacetate is reduced to malate and pyruvate to lactate , depleting gluconeogenic substrate.
  56. Front
    High NADH from ethanol shifts pyruvate to lactate , causing which acid-base disturbance?
    Back
    Lactic acidemia (lactic acidosis) .
  57. Front
    Why does chronic ethanol cause fatty liver disease ?
    Back
    High NADH suppresses β-oxidation and the TCA cycle , so fatty acids accumulate in hepatocytes.
  58. Front
    Which purine-derived metabolic abnormality results from increased uric acid synthesis during ethanol metabolism?
    Back
    Hyperuricemia .
  59. Front
    Increased triglyceride synthesis and VLDL export during ethanol metabolism cause which lipid abnormality?
    Back
    Hyperlipidemia .
  60. Front
    Which toxic ethanol intermediate reacts with proteins and depletes GSH , causing hangover nausea and headaches?
    Back
    Acetaldehyde .
  61. Front
    What toxic intermediate is formed when acetaminophen is oxidized by CYP2E1 ?
    Back
    NAPQI (normally quenched immediately by GSH ).
  62. Front
    Why are alcoholics at high risk of hepatotoxicity from even therapeutic doses of acetaminophen ?
    Back
    Double jeopardy : CYP2E1 is induced (more NAPQI produced) AND acetaldehyde depletes GSH (less NAPQI quenched).
  63. Front
    Besides hypoglycemia, lactic acidemia, fatty liver, hyperuricemia, and hyperlipidemia, what is the sixth NADH -driven metabolic consequence of chronic ethanol ?
    Back
    Ketoacidosis (high NADH suppresses the TCA cycle and β-oxidation, acetyl-CoA builds up, and ketone bodies are generated).
  64. Front
    Mechanistically, why does the NADH flood from ethanol cause ketoacidosis ?
    Back
    High NADH inhibits the TCA cycle and β-oxidation , so acetyl-CoA accumulates and is diverted to ketone-body synthesis.
  65. Front
    How many oxidative pathways metabolize ethanol in the liver , and what are they?
    Back
    Three : alcohol dehydrogenase (ADH, major) , the Microsomal Ethanol Oxidizing System (MEOS/CYP2E1) , and catalase (minor in liver).
  66. Front
    Which is the THIRD ethanol -oxidizing pathway, quantitatively minor in the liver but responsible for ~60% of ethanol metabolism in the brain ?
    Back
    Catalase .
  67. Front
    What structural feature in the CYP active site binds O₂ and is the signature of the entire cytochrome P450 superfamily?
    Back
    An iron-heme .
  68. Front
    Beyond CYP1A1 , induction of which enzyme by chronic drinking also raises cancer risk in alcoholics, and why?
    Back
    CYP2E1 — when induced it metabolizes procarcinogens more aggressively.
  69. Front
    First-pass CYP3A4 normally lets only about what fraction of an oral dose survive into the portal vein?
    Back
    About 30% .
  70. Front
    Because first-pass CYP3A4 normally lets only ~30% of a dose through, inhibiting it (e.g., grapefruit juice ) produces roughly what general increase in bioavailability of CYP3A4 substrates?
    Back
    About a 3-fold increase in bioavailability.
  71. Front
    Besides statins, name the high-risk CYP3A4 substrates whose levels grapefruit juice can dangerously raise.
    Back
    Calcium channel blockers, cyclosporine, diazepam, sildenafil, methadone, and saquinavir .
  72. Front
    Roughly how many CYP genes and isoforms does the human genome contain?
    Back
    About 60 CYP genes , yielding over 150 isoforms .
  73. Front
    Which three CYP families are the most relevant to drug metabolism?
    Back
    CYP1, CYP2, and CYP3 .
  74. Front
    When CYP enzymes are induced , their activity rises by roughly how much, and over what time course?
    Back
    About 3–4-fold within days , primarily by increased gene transcription.
  75. Front
    A single 250 mL glass of grapefruit juice reduces intestinal CYP3A4 levels by roughly what percentage, and how quickly?
    Back
    By about 47% within four hours .
  76. Front
    Besides hydroxylation, name two other oxidative reactions cytochrome P450 can perform in Phase I .
    Back
    Epoxidation and deamination (CYP can also perform other oxidative modifications).
  77. Front
    Under normal conditions, which two Phase II routes dominate acetaminophen metabolism, and only what fraction is oxidized to toxic NAPQI ?
    Back
    Sulfation and glucuronidation dominate; only about 5% is oxidized (by CYP2E1 ) to NAPQI , which is immediately quenched by GSH .
  78. Front
    Alcohol dehydrogenase (ADH) is found mainly in the liver but also in which other tissue?
    Back
    Gastric mucosa (gastric ADH).
  79. Front
    At moderate drinking levels, roughly what fraction of ethanol does the MEOS (CYP2E1) pathway handle?
    Back
    About 10–20% ( ADH handles the majority at moderate intake).
  80. Front
    What fraction of ingested ethanol is exhaled or excreted unchanged in the urine?
    Back
    About 2–10% (the basis of breath/urine alcohol testing).
  81. Front
    Despite ethanol's real caloric value (7.1 kcal/g), why do alcoholics develop vitamin deficiencies and undernutrition ?
    Back
    Impaired nutrient absorption plus secondary liver and pancreatic damage (ethanol provides 'empty calories').

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