Lect. No. 14 & 15 Detoxification & Biotrasformation of Xenobiotics.ppt
Drugmetabolism
1. 11/06/08 Discussion - ALL
SEC TIONS MEET IN
ROOM 107
Hintsfor making a clear
group presentation
11/11/08 Peterson Prions and protein
folding
11/13/08 Discussion Work in groups on your
group presentations
11/18/08 Bryk HIV/AIDS
11/20/08 Group presentations -
meet inyour discussion
room
Student presentations
11/25/08 Group presentations -
meet inyour discussion
room
Student presentations
11/27/08 Thanksgiving No class
12/02/08 Group presentations -
meet inyour discussion
room
Student presentations
12/05/08 Final Exam 3 -5 PM
Room 107
Final exam
3. Grapefruit and drugs a potent mix
McGill University Health Centre Journal
Grapefruits are chalk full of vitamin C, potassium and natural fiber. So they have to
be good for you, right? Well, not necessarily.
Taking a swallow of grapefruit juice to down your prescription medication could play
havoc with the digestion of certain drugs, increasing the amount of medication
released into the bloodstream, which could lead to harmful levels or drug toxicity.
To complicate matters, if you have always enjoyed a glass of grapefruit juice,
stopping this habit could cause the opposite effect, your body will absorb too little
medication.
6. Cytochrome P450
Enzyme found mostly in liver
-steroid hormone biosynthesis from cholesterol
-metabolism of xenobiotics-compounds which are not normally found in
the body
-Drugs
-Compounds in food produced by cooking (polyaromatic hydrocarbons,
also in tobacco smoke) or microorganisms
Cytochrome P450 has a wide range of roles
-typically organic molecules which are poorly soluble in water
7. The OH added by P450 can then be used to attach sulfate (SO4
2-
) or a sugar.
The modified drug can be more readily removed by the kidney.
Cytochrome P450 aids in the metabolism of xenobiotics by adding OH to
increase the water solubility of the compound
O2 + substrate + 2 electrons
HO-substrate + H2O
Because this enzyme catalyzes the addition of one oxygen atom, it is
termed a monooxygenase.
8. N
NN
N
Fe
Heme
The heme group is a cofactor which contains iron.
Different forms of heme are found in hemoglobins and proteins
known as cytochromes.
The iron in a heme can bind oxygen and transfer electrons.
Cytochrome P450 contains heme.
9. Cytochrome P450’s are integral membrane proteins found in the endoplasmic reticulum-
membrane network in cells
Cytochrome P450
11. Cytochrome P450
At least 57 different isozymes in humans, over 7700 forms in Nature
isozyme-catalytically and structurally similar but genetically
distinct enzymes-different genes and amino acid sequences
Different isozymes have different substrate specificities
Individuals have several alleles for P450’s and differ in which isozymes they
have
A subset of cytochrome P450’s can be induced, so that more is expressed upon
exposure to a compound.
Because of the number of different isozymes and their different substrates and
inhibitors, the metabolism of a drug can be altered if an individual takes a second
drug.
Since individuals have different combinations of P450’s, they differ in their response
to specific drugs
16. The reaction of cytochrome P450 can also produce a toxic compound:
HN
C
CH3
O
Acetaminophen
OH
At normal doses, sulfate or a sugar is attached to OH and the drug is easily removed
by the kidney.
At high doses, this pathway cannot keep up and a liver P450 converts acetaminophen
to a toxic metabolite which causes liver damage.
Metabolism of acetaminophen (Tylenol)
18. Several important neurotransmitters are amines.
NH3
HO
HO
dopamine
NH3
HO
HO
norepinephrine
NH2
HO
HO
epinephrine
OH
CH3
NH3
NH3
N
H
HO
serotonin
These are released into the blood where they bind to receptors on
the surface of cells.
To ensure that the action of amine neurotransmitters is short, they are
destroyed by the enzyme monoamine oxidase.
19. Monoamines also come from the diet
NH3
HO
tyramine
Tyramine is formed from tyrosine. If blood levels rise they disrupt catecholamine
metabolism, leading to possibly fatal hypertension. Monoamine oxidase prevents
this.
Foods containing high levels of tyramine:
smoked, aged, or pickled meat or fish; sauerkraut
aged cheeses (e.g., swiss, cheddar, blue, boursault, camembert, emmenthaler, stilton);
yeast extracts
fava beans
beef or chicken liver
aged sausages (e.g., bologna, pepperoni, salami, summer sausage)
game meats (e.g., venison, rabbit)
red wines (e.g., chianti, sherry).
20. Monoamine oxidase
An integral membrane protein in liver mitochondria.
Oxidizes amines to aldehydes:
NH3
HO
HO O2
O
HO
HO
+ NH4
21. Monoamine oxidase contains FAD as a cofactor
N
NH
N
O
O
R'
N
Flavin Adenosine Dinucleotide
Synthesized from the vitamin riboflavin
Used in electron transfer reactions
23. Monoamine oxidase (MAO) inhibitors are used as antidepressants and to
treat eating disorders.
They keep serotonin levels up. Serotonin controls mood.
MAO inhibitors can cause overdoses:
No longer break down tyramine from diet.
High levels of tryptophan in diet can result in serotonin levels becoming too high.
Will prevent metabolism of drugs that are amines. As a result MAO inhibitors can
result in serious side effects when used with other drugs.
MAO inhibitors have been replaced with drugs which prevent the binding of serotonin to cells,
such as Prozac. These do not affect the metabolism of other amines, so that there are far
fewer side effects.
Monoamine oxidase inhibitors
