EXAM 5 - Drug Metabolism 3 Flashcards
What 3 enzymes are involved with oxidation phase 1 reactions?
- alcohol dehydrogenase
- aldehyde dehydrogenase
- peroxidase-dependent co-oxidation
- Cytochrome P450
Describe alcohol dehydrogenase oxidation reaction.
- cytosolic
- highest levels in the liver
- alcohol –> aldehyde
Describe aldehyde dehydrogenase oxidation reactions.
- some people have inactive ALDH2 –> in the body ALDH2 converts ADH to acetic acid –> ADH builds up in the body –> flushing syndrome
- alcohol –> aldehydes and carboxylic acid
Describe the mechanism of prostaglandin H-synthase during acetaminophen metabolism.
- reduces peroxide to alcohol
- oxidizes acetaminophen –> creates free radical (can damage the kidney)
Describe Prostaglandin H-synthase enzyme of phase 1 oxidation.
Peroxidase-dependent Co-oxidation
* Metabolizes arachindonic acid
Two types of PHS: Cox-1 and Cox-2
* each have two components: cyclooxygenase and peroxidase
What is the function of the cyclooxygenase component of Cox-1 and Cox-2?
Metabolizes arachidonic acid and two molecules of oxygen to form PGG2.
What is the function of the peroxidase component of Cox-1 and Cox-2?
Reduces peroxide to alcohol PGH2.
* Oxidation of something (like acetaminophen)
* oxidation can cause toxicity
What was the thinking process behind developing Vioxx as an anticancer drug?
The peroxidase reactions cause oxidation of compounds that produce toxic substances/free radicals –> may cause cancer.
* if a drug is designed to block the production of reactive compounds. –> prevent cancer
Define cytochrome.
Red, heme-containing proteins.
* when bound to carbon monoxide, it absorbs light at 450 nm.
What enzyme or class of enzymes is responsible for the majority of drug metabolism?
CYP450 enzymes.
Explain the nomenclature of CYP450s.
Explain the nomenclature of CYP450s.
How many CYP genes/pseudogenes do humans have?
> 50 CYP genes
>50 pseudogenes
List the types of reactions catalyzed by P450s.
- Hydroxylation of an aliphatic or aromatic carbon
- epoxidation of a double bond
- heteroatom (S-, N-, I-) oxidation and N-hydroxylation
- heteroatom (O-, S-, N-, and Si-) dealkylation
- oxidative group transfer [heteroatom (N, S, or halogen) is replaced with oxygen]
- cleavage of esters
- dehydrogenation
Identify this type of reaction catalyzed by P450s.
Hydroxylation of an aliphatic or aromatic carbon.
Identify this type of reaction catalyzed by P450s.
Epoxidation of a double bond.
Identify this type of reaction catalyzed by P450s.
Heteroatom (S, N, and I) oxidation and N-hydroxylation.
Identify this type of reaction catalyzed by P450s.
Heteroatom (O, S, N, and Si) dealkylation
* methanol is oxidized to formaldehyde
Identify this type of reaction catalyzed by P450s.
Oxidative group transfer
* heteroatom (N, S, or halogen) is replaced with oxygen
Identify this type of reaction catalyzed by P450s.
Cleavage of esters
* instead of alcohol and acid (esterase)
* you have aldehyde and acid (P450)
Identify this type of reaction catalyzed by P450s.
Dehydrogenation
What is located at the center of cytochrome P450 compounds?
Heme group (Fe3+ with 4 surrounding N molecules)
* heme held in the catalytic site through hydrogen bonding by surrounding carboxylic acid groups
Explain the catalytic mechanism cycle of cytochrome p450s.
- When Fe3+ is reduced to Fe2+, the P450 an bind ligands such as O2 and CO.
- starts with heme group w/ Fe3+ center –> substrate binds catalytic site near the Fe3+
- electron comes in and reduces Fe3+ to Fe2+ (electron comes from another enzyme (NADPH-CYP450 reductase)
- Fe2+ can now bind to oxygen (or CO)
- another electron comes in to reduce oxygen to peroxide
- water leaves
- substrate RH gets oxidized (hydroxylation step) –> ROH
- product ROH leaves
What is the overall reaction equation of CYP450?
