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13 Cards in this Set

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Explain the basic mechanisms of drug metabolism.
Phase 1 - catabolism, increase drug's hydrophilicity through either oxidation/reduction of hydroxylation. Introduction of a reactive group as a point for conjugation in phase 2.

Phase 2 - Anabolism, conjugation through glucuronidation or sulphanation. This increases solubility.
Define phase I and phase II reactions.
Covered on #2
Describe the role of cytochrome P450 enzymes in drug metabolism.
Hydroxylation of steroids
Liver hydroxylates cholesterol in bile acid synthesis
Detoxification of drugs and xenobiotics using NADP as reducing equivalent
New hydroxyl groups on drugs provide conjugation sites for phast 2 reactions.

Mechanism - RH + O2 + NADPH H+ → R-OH + H2O + NADP+

* The use of NADPH and not NADH is important.
Outline the different human P450 families and their main functions.
CYP1 drug and steroid (especially estrogen) metabolism
CYP2 drug and steroid metabolism
CYP3 drug and steroid (including testosterone) metabolism
CYP4 arachidonic acid or fatty acid metabolism
CYP5 thromboxane A2 synthase
CYP7 bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus
CYP8 varied
CYP11 steroid biosynthesis
CYP17 steroid biosynthesis, 17-alpha hydroxylase
CYP19 steroid biosynthesis: aromatase synthesizes estrogen
CYP20 unknown function
CYP21 steroid biosynthesis
CYP24 vitamin D degradation
CYP26 retinoic acid hydroxylase
CYP27 varied
CYP39 7-alpha hydroxylation of 24-hydroxycholesterol
CYP46 cholesterol 24-hydroxylase
CYP51 cholesterol biosynthesis
Describe the mechanisms of enzyme induction and enzyme inhibition and their clinical consequences.
Induction occurs at genetic level.
1. Drug binds to hepatic xenobiotic receptor
2. Complex translocates to nucleus
3. Complex binds to gene promoter for specific enzyme
Outline the genetic polymorphisms of cytochrome P450 and their clinical implications.
Polymorphism is variability of a gene within 1%. This is responsible for differing responses to the same drug.

Slow Metabolism - high plasma levels
Fast Metabolism - drugs ineffective at low/normal doses
Describe examples of cytochrome P450 detoxification reactions (Aflatoxin B1 and acetaminophen metabolism).
Acetaminophen - Glucoronidated or sulfated and passed through urine.

Aflatoxin B1 - I see no information on this.
Describe the mechanism of acetaminophen toxicity and the biochemical basis for its management.
5% metabolized by CYP2E1, producing NABQI, a potent oxidator. Overdose will overpower detox conjugation ability causing hepatocelluar membrane damage. Ethanol up-regulates CYP2E1 and leads to this problem as well.
Describe the routes for ethanol metabolism. Discuss the role of alcohol dehydrogenase, acetaldehyde dehydrogenases, and the microsomalethanol oxidizing system in the metabolism of ethanol.
Route 1 - Microsomal ethanol oxidising system (MEOS) - CYP2E1 metabolises ethanol like alcohol dehydrogenase, turning NADPH to NADP+.

Route 2 - Dominant - Alcohol dehydrogenase (ADH)
Alcohol and acetaldehyde dehydrogenase - converts ethyl alcohol to acetaldehyde creating NADH. NADH accumulation enhances lactate production over pyruvate. ↓ gluconeogenesis, acyl β-oxidation, oxalacetate, glucose to brain (hypoglaecimia) ↑ lactic acidosis, ketoacidosis, TAG synthesis & VLDL production.

Route 3 - Catalase (insignificant)
Outline the fate of acetate formed from ethanol
Alcohol dehydrogenase (ADH) → Acetaldehyde → Aldehyde dehydrogenase → Acetic acid → Acetyl CoA → TCA cycle or lipid synthesis
Discuss the physiological relevance of induction of CYP2E1 by ethanol.
Ethanol increase of CYP2E1 increases NABQI levels causing liver necrosis.
Describe the biochemical basis for the acute and chronic toxic effects of ethanol abuse.
See #10