Lecture 36: Drug Metabolism and Detoxification

we dont

How do we tell the difference between a toxin and a drug?

lipophilic (hydrophobic)

Most waste products, toxins, drugs are too ________________ to be eliminated

Not readily soluble in the blood or urine to move them through the body and they get stuck

Lipophilic molecules are harder to eliminate, why?

add polar groups

How can molecules be changed to reduce their hydrophobicity?

the molecule will become more reactive

what are the risks associated with adding functional groups

polar (hydrophilic)

The way that the body makes these drugs and waste products more hydrophilic, we add a ___________ group

lose control

The danger of making modifications to make substances more hydrophilic is that the body can ______ ____________ and make them hihgly reactive

liver

The ____ is the most important organ in detoxification

Phase I

this phase of detox is hydroxylation using cytochrome p450

to expose or add the initial functional group (the group we want to get rid of)

what happens in Phase I

Makes a group that is somewhat more polar, makes it more reactive for the next phase

What is the outcome of phase 1

Phase II

this phase of detox is conjugation reaction that adds the charged/polar group

Water solubility

Phase 2 is important for increasing the _____ _______ of the compound

O2

Many Phase I reactions feature an __ - dependent hydroxylation

Hydroxylation - adding OH group

Conjugation - adding a group to make it more soluble

Phase I = _______

Phase 2 = ________

4

_____ electrons in total are required for the splitting of O2

water

the 4 electrons for detox come from O2 and _________

monohydroxylations

most oxygen consuming hydroxylations are ________

iron

most monohydroxylations include an ___ ion in the active site to facilitate oxygen binding

Transferases

After the nonpolar molecule is oxygenated, the charged/polar substance are added by ____________(hwat class of enzyme?)

high

erythrocytes have a ____(high/low) turnover rate

Protein component, heme

these two parts of hemoglobin need to be metabolized/secreted as a waste product

heme interacts with oxygen and we dont want it bouncing arounf interacting with random e-

what is the potential danger of unprocessed heme?

bilirubin

heme produced on the death of erythrocytes is processed to ______ in 2 steps

biliverdin

in step one heme oxygenase converts heme in a linear tetrapyrrole called

Biliverdin

this is a bile pgiment (green) commonly seen after heme oxygenase lineraizes heme to form it, seen green color after bruising

bilirubin

In step 2 biliverdin reductase converts biliverdin into _______

bilirubin

biliverdin reductase converts viliverdin into this, a yellow compound, which travels bound to albumin, brought to liver where it is more soluble

NADPH

what is the electron donor in the formation of bilirubin

conjugation

the solubility of bilirubin in the liver is increased by _______, which adds glucuronic acid

unconjugated or indirect bilirubin

conjugated or direct bilirubin

the bilirubin population in the blood is often divided into two categories

unconjugated or indirect bilirubin

which form of bilirubin is carried by serum albumin

conjugated or direct bilirubin

which form of bilirubin does not require albumin

total

_____ bilirubin is the sum of direct and indirect bilirubin

greater unconjugated means liver damage

what disorders could increase the unconjugated to conjugated bilirubin ratio

urobilinogen

bilirubin in the intestine is processed into

urine

some urobilinogen is converted to urobilin which gives the color and is secreted in the_____

feces

some urobilinogen remains in the intestine and is converted to stercobilin which gives the color to and is excreten in the

jaundice

this is caused by bilirubin accumulation, results from imparied liver, blocked bile secretion, insufficient glucuronyl bilirubin transferase to rpocess bilirubin, yellowish skin and eyes

Cytochrome p450

this class of enzyme play a big role in drug metabolism

phase I

Cytochrome p450 enzymes carry out the majority of _____ __ reactions

biosynthetic processe

this class of cytochrome P450 enzymes are generally single substrate enzymes for making molecules

Detoyifying reactions

this class of cytochrome P450 enzymes are generally multiple substrate enzymes, work in the mitochondria to get rid of toxins

NADPH

this is the electron source for P450, which eventaully gets hyroxylated substrate and water

Acetaminophen

this is tylenol, helps with pain or inflammation

conjugation, excretion

the major pathway of acetominophen degredation involves _____ followed by____

NAPQI, glutathione

The minor pathway of acitaminophen produces a lot of ____________, which is toxic, and it also conjugates _______________

1 and 2

the minor pathway uses both phase _____ and ____

minor

problems occur when the _____ path increases

decreases

In acetaminophen consumption, glutathione in the cell ______________(increases/decreases)

Glutathione

this helps prevent oxidative damage, gets used when metabolizing acetaminophen

Increase, decrease

In general, acetaminophen toxcity will cause teh amoutn of NAPQI to ___________(increase/decrease), which causes glutathione to __________(increase/decrease), which means taht NAPQI will be toxic to other things, causing hepatocyte necrosis and oxidative damage

CYP2E1, increases

When drinking, ethanol induces prdouction of ____________, which ____________(increases/decreases) NAPQI a lot, which makes it so that acetaminophen can be toxic even at _________ doses

Activate, degrade

P450 works in drug metabolism by sometimes ____________ drugs like with codein or losartan, but also can be used to ________________ things, like warfarin and other anticoagulants