LMP301H1 Lecture Notes - Lecture 19: Aldehyde Dehydrogenase, Codeine, Hydrophile

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Published on 14 Sep 2016
School
Course
Professor
LMP301
Introduction to the Biochemistry of Human Disease
Lecture 19 Toxicology
I’m slightly intoxicated right now so excuse the typos and comments (profanity might be involved)
Biotransformation (mostly liver)
o Convert lipophilic to hydrophilic molecule aids in elimination
Reduction, oxidation, hydrolysis, conjugation
o Phase I by P450s (which are inducible, inhibitable, and genetically polymorphic)
Zone 3, mitochondria
1. Drugs binds P450-Fe3+ complex
2. Add e- to make Fe2+
3. Reoxidize (O2)
4. Restore P450-Fe3+ and get oxidized drug (sometimes this makes an electrophilic
compound that fucks up DNA and proteins; actually most of drug bioactivation
to a more harmful compound is due to P450s, you’d almost think they’re the bad
guys)
o Phase II
Conjugation in kidney and liver
Glucuronidation by glucuronsyl transferase
Elimination mainly by kidney (some intestine via bile, also breath, saliva, breast
milk but not for men)
Case study: codeine (don’t take this while drunk, like my friend did, but she survived thankfully)
o Metabolized by CYPs
(2D6) O-demethylation morphine
(3A4) N-demethylation norcodeine
Conjugation with glucuronides and sulfates
Mostly norcodeine-6-glucuronide
Ethanol metabolism (hehe)
o Normal: ethanol acetaldehyde (alcohol dehydrogenase in cytosol) acetate
(aldehyde dehydrogenase in mitochondria) Kreb’s cycle
o Acetaldehyde is toxic
o Use of Kreb’s cycle forces glucose to go into lactate cycle metabolic acidosis
o Also use of Kreb’s cycle depletes NAD accumulation of Acetyl-CoA forces FA
metabolism fatty liver (like your mom)
o Chronic use
Acetaldehyde immune response inflammation
intestinal permeability endotoxins Kupffer and immune
inflammation and Stellate (fibrosis) = RIP liver XP
- slide 25 (don’t quote things you don’t know)
MDMA MDA (N-demethylation)
o Synthetic derivative of meth (I’m not high, just drunk. I don’t know where to get meth
anyway)
o Increased alertness, energy, euphoria, sociability
o Temperature is a major determinant of overdose survival rate
o Phase I: to MDA, HHMA, HHA
o Phase II: to glucuronide, sulfate, and GSH conjugates urine excretion
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