DILD and DM- Austin- EXAM 3

What is a xenobiotic?

a foreign substance to the body (ex: drug)

Where is the primary site of metabolism? Where are other sites?

primary- liver

other: GI wall

How many phases to metabolism are there? What type of reactions belong to each?

• Phase I- oxidation, reduction, hydrolysis

• Phase II- conjugation

Phase I produces what kind of metabolites?

inactive, active, or TOXIC

Phase II produces what kind of metabolites?

inactive, NONTOXIC

What is the rate of phase I and phase II reactions? slow or fast

phase I- slow

phase II- fast

What is the capacity of phase I and phase II reactions?

phase I- infinite

Phase II- limited

What are the requirements for an oxidation reaction?

• oxidizing agent (O2)

• enzyme

• substrate/drug

• sometimes cofactor

What ENZYMES are used in oxidation reactions?

• CYTOCHROME P450 SUPERFAMILY aka CYP enzymes

• others: MAO, FMO, ADH

What are some common examples of oxidation reactions?

• aliphatic/aromatic hydroxylation

• N or S oxidation

• N, O, S dealkylation

• N-deamination

Why is there only N or S oxidation and not O oxidation?

can’t oxidize an oxygen

What type of reaction is this:

aliphatic hydroxylation

What type of reaction is this:

aromatic hydroxylation

What type of reaction is this:

N-oxidation

What type of reaction is this:

S-oxidation

What type of reaction is this:

N-dealkylation

What type of reaction is this:

O-dealkylation

What type of reaction is this:

S-dealkylation

What type of reaction is this:

Deamination

Hydrolysis is another type of Phase I reaction. What groups does this usually occur on?

esters and amides

What type of reaction is this:

hydrolysis (ester)

What type of reaction is this:

hydrolysis (amide)

What is a conjugation reaction?

attaching hydrophilic molecules to drug molecules/metabolites by formation of a covalent bond

In a phase II conjugation reaction, the conjugate usually replaces…

a hydrogen covalently bonded to a heteroatom

A conjugation reaction requires a ____________ enzyme.

transferase

What are some examples of conjugates?

• glucuronate- MOST COMMON

• glutathione

• others: sulfate, AA, acetyl, methyl

What enzyme is needed in a glucuronidation?

UDP glucuronosyltransferase

What do phase II reactions require?

• conjugate

• drug

• transferase enzyme

What are the 6 mechanisms of toxicity in DILD?

1. stimulation of autoimmunity

2. idiosyncratic rxns

3. disruption of Ca++ homeostasis & cell membrane injury, transport proteins & cell communities

4. cytochrome P450 mediated

5. mitochondrial injury

6. liver neoplastic disease

What are the 2 MECHANISMS that stimulate autoimmunity? (this leads to DILD)

1. enzyme-drug adducts migrate to cell surface and form neoantigens

   • happens immediately and are targeted by Kupffer cells and cytotoxic killer T-cells

2. chronic active hepatitis- takes long time

   • takes long time and formation of anti-organelle and antinuclear Abs

What drugs are associated acute autoimmune injury ?

• TNF-a inhibitors

• carbamazepine

• fluoroquinolones

• halothane

• nevirapine

• sulfamethoxazole

What drugs are associated with chronic active hepatitis?

• dantrolene

• isoniazid

• methyldopa

• nitrofurantoin

• phenytoin

• trazodone

What are the 2 types of idiosyncratic rxns? What are some examples of drugs that belong to each?

allergic (HLA phenotypes)- minocycline, augmentin, allopurinol

nonallergic- amiodarone, ketoconazole

What drugs can cause a disruption of Ca++ homeostasis and cell membrane injury and lead to DILD?

lovastatin and venlafaxine

What drugs can effect transport proteins and cell communities and lead to DILD?

glimepiride (inhibit BSEP) and metformin (MATE2)

What are Kupffer cells?

local immune cells—> macrophages that help remove debris and initiate the immune response

What are some drug examples of cytochrome P450 mediated DILD?

• Acetaminophen

• furosemide

• diclofenac

How is APAP normally metabolized? (include all 3 pathways)

• 80-90% goes glucuronidation and conjugation

• other 10% goes through OXIDATION and forms the toxic metabolite NAPQI

• NAPQI is inactivated by glutathione

What happens in toxic/large doses of APAP?

• phase II is saturated/ more APAP goes thru oxidation pathway

• not enough glutathione to inactivate the toxic metabolite NAPQI

Why is the risk of hepatotoxicity with APA higher if you drink alcohol?

• lowers toxic threshold

• give preference to NAPQI

The max daily dose of APAP is ___ g.

4

What is the antidote to APAP? How does it act?

N-acetylcysteine- acts like glutathione

What are some drug examples that can cause mitochondrial injury and lead to DILD?

• aspirin

• valproic acid

What are some drug examples that can cause liver neoplastic disease and lead to DILD?

androgens, estrogens, and other hormone agents

THINK: HORMONE DRUGS