Biotransformation

Question 1

Name some organs, which express P450 isozymes involved in drug metabolism

Answer 1

Liver, kidney, skin, intestine + lungs

Question 2

What is the electron donor for monooxygenases in drug metabolsim?

Answer 2

NADPH

Question 3

What kind of ROS can be formed during P450 monooxygenation?

Answer 3

Superoxide (O2-)

Question 4

Which pathways of the intermediary metabolism involve biotransformation reaction?

Answer 4

Bile acid, Steroid hormones synthesis, cholesterol synthesis, D-vitamin, Catacholamines, Drugs

Question 5

Which phase of biotransformation is mediated by transports?

Answer 5

Phase 3

Question 6

What is the dominant chemical reaction in 1st phase of biotransformation?

Answer 6

Hydrolysis, oxidation, hydration, reduction

E.g. Hydroxylation

Formation of a more water soluble drug

Question 7

Which enzyme catalyse the majority of the reactions in 1st phase biotransformation?

Answer 7

CYP P450 monooxygenase complex families

Question 8

What kind of solubility change is caused by transformation reaction?

Answer 8

A substance is transformed into a more water soluble substance, which can be excreted

Question 9

What is the first enzyme component of the microsomal respiratory chain and what is the electron donor?

Answer 9

Enzyme: Cytochrome P450 reductace
Donor: NADPH

Question 10

What are the 3 phases of biotransformaition?

Answer 10

1: Oxidation
2: Conjugation
3: Transporters

Question 11

What is the general reaction of CYPs?

Answer 11

R-H + 02 + NADPH + H+ -> R-OH + H2O + NADP

Question 12

How many CYP families do we have in drug metabolism?

Answer 12

4 families: 1, 2, 3, and 4

Question 13

Name 1 very important function of the liver?

HINT: portal circulation

Answer 13

First pass effect

Question 14

CYP1: Is it inducible and what is its substrate?

Answer 14

Yes, by dioxin derivatives

Substrate: Policyclic aromatic hydrocarbons (PAH)

Question 15

CYP2: Is it inducible and what is its substrate?

Answer 15

Yes, by ethanol, aceton phenobarbital and diazepam derivaties .

Many different substrates depending on sub-family type.
We have CYP2A, 2B, 2C and 2D

Question 16

Name some nuclear receptors in drug metabolism

Answer 16

CAR: androstanes, phenobarbital
LXR: Oxysterols
RXR: Pregnanes
PPAR alpha, beta, gama: fatty acids, eicosanoids

“gene battery”: For phase 1+2 reactions and ABC transporters for phase 3

Question 17

What is the most common type of conjugation?

Answer 17

Glucuronidation (UDP-glucuronate -> by UDP-glucuronosyl transferase (UGT))
Other reactions: Sulfunation, glutathione conjugation, amino acid conjugation, methylation, acetylation.

Sulfunation with PAMS by sulfotransferase
Glutathione conjugation:

Question 18

Which receptor mediates dioxin toxicity?

Answer 18

Aryl Hydrocarbon receptor (AhR)

Question 19

Whats the effect of hypertriglycedemia on size and density of LDL?

Answer 19

Size: decrease
Density: increase

Question 20

Which phase of biotransformation is mediated by transporters?

Answer 20

III. phase

Question 21

Dominant chemical reaction in 1st phase of biotransformation?

Answer 21

OXYGENATION

Question 22

What kind of metabolizer phenotypes are known due to SNPs of drug metabolizing enzymes?

Answer 22

People having Gilberts disease (unconjugated hyperbilirubinemia) due to SNP’s (single nucleotide polymorphism) in the promoter region of UGT (UDP-­‐ gucuronyltransferase) genes.

Poor metabolizers, extensive metabolizers

Question 23

Co- factor of glucoroniditation?

Answer 23

UDP- glucoronic acid

Question 24

Which enzymes catalyzes glucorunidation?

Answer 24

UDP- glucoronidate transferases (UGT)

Question 25

Most important ligands of nuclear receptors

Answer 25

Hormones, Drugs, Vitamins, Eicasonoids

Question 26

Where are the steroid receptors before ligand binding in the cell?

Answer 26

On the PM, cytosol, nucleus (generally intracellular)

Question 27

List at least two types of pattern recognition receptor involved in the pathomecanism of arthrosclerosis

Answer 27

SCAVANGER r.s., TLRs, NLRP

Question 28

Which are the most important xenobiotic inducers of CYP1 isoenzymes?

Answer 28

Polycyclic Aromatic Hydrocarbons

Question 29

Dominant type of conjugation in case of electrophilic intermediates?

Answer 29

Glutathion conjugation

Question 30

First component of microsomal respiratory chain

Answer 30

NADPH- p450- oxidoreductase

Question 31

Mutation of which receptor are underling the testicular femination syndrome?

Answer 31

Androgenic

Question 32

Conjugated hyperbilrubinemias are caused by? what is the name of the syndromes?

Answer 32

Transport of conjugated bilrubin is disturbes. Transport problems. Dubin-Johnsons syndrome Rotor syndrome

Question 33

What do we need for sulfuration?

Answer 33

PAPS (3'-phosphoadenosine-5'-phosphosulfate)