1 metabolism II

Question 1

what is the purpose of phase 2?

Answer 1

-the major increase in water solubility (and this excretability) of xenobiotics occurs after Phase II reactions, which add (conjugate) a large water-soluble group to an existing polar functional group on the molecule

Question 2

what is glucuronidation?

Answer 2

-the major phase II biotransformation pathway in mammals
-requires enzyme UDP- glucuronosyl transferase (UGT) and cofactor UDP-glucuronic acid
-located on smooth ER membrane (other phase 2 enzymes are located in cytoplasm)

Question 3

what is sulfation?

Answer 3

-enzyme sulfotransferase (ST) and cofactor PAPS
-located in cytoplasm

Question 4

what is acetylation?

Answer 4

-enzyme N-acetyltransferase (NAT) and cofactor acetyl coenzyme A
-located in cytoplasm

Question 5

what is an example of a biotransformation of phenytoin?

Answer 5

an anticonvulsant drug
-involves phase 1 and 2 enzymes

Question 6

why is glutathione conjugation such an important enzyme?

Answer 6

one of our most important defenses against reactive electrophiles (reactive oxygen species and epoxides)
-4th phase 2 enzyme

Question 7

what is glutathione conjugation?

Answer 7

enzyme: glutathione S-transferase (GST)
-abundant enzyme, approximately 5% of cytosolic protein in liver cells

cofactor: glutathione (GSH)
-mM concentrations in most cells (very high concentration)

Question 8

what are reactive oxygen species and epoxides?

Answer 8

Question 9

what are glutathione conjugates rearranged to ?

Answer 9

glutathione conjugates are rearranged to mercapturic acid and commonly excreted in bile

Question 10

what is the graph of acetaminophen biotransformation?

Answer 10

Question 11

why shouldn’t we take tylenol if we have a hangover?

Answer 11

Question 12

what is the biotransformation summary?

Answer 12

Question 13

what is biotransformation :) vs :(?

Answer 13

Question 14

what are the genetic and environmental factors influencing biotransformation?

Answer 14

1. enzyme induction and inhibition
2. intraspecific differences
3. interspecific differences
4. sex and age
5. diet (nutritional factors)
6. disease (underlying pathology)

Question 15

what is enzyme induction and inhibition?

Answer 15

-CYP enzymes and phase 2 enzymes can all be induced (Increased activity) and inhibited (decrease activity)
-very toxicologically relevant with respect to duration of xenobiotic action and xenobiotic interactions
-depletion of cofactors (ex: glutathione) can also be very important

Question 16

what is intraspecific differences?

Answer 16

-genetic differences (polymorphisms) in the expression of enzymes
-can result in a subset of the population being “poor metabolizers” or even “rapid metabolizers”
-classic example is alcohol dehydrogenase (ADH) in humans

Question 17

what are interspecific differences?

Answer 17

-examples: cats are poor glucuronidators (UGT), dogs are poor acetylators (NAT), and pigs are poor sulfators (ST)

Question 18

what is sex and age?

Answer 18

-sex-specific differences in certain CYP enzymes
-in general very young and old individuals have lower enzyme activities

Question 19

what is diet?

Answer 19

-certain dietary ingredients can induce or inhibit phase 1 or phase 2 enzymes (ex: grapefruit juice inhibits CYP3A4 in humans)

Question 20

what is disease?

Answer 20

-impaired liver function can decrease biotransformation of xenobiotics

Question 21

what is the table of species differences of sleeping time after injection of hexobarbital (a sedative)

Answer 21

Question 22

what is the table of species differences in glucuronidation and sulphation?

Answer 22

Question 23

what is the summary of phenytoin biotransformation?

Answer 23

a patient has epilepsy and you prescribe phenytoin daily. apply your knowledge of biotransformation to consider the outcomes of drug therapy in the following scenario
-induction of CYP or UGT
-inhibition of CYP or UGT
-enzyme polymorphism for CYP or UGT
-the patient is a cat
-the patient is very young or very old
-the patient has a liver disease such as hepatitis or cirrhosis

Question 24

what is the summary of acetaminophen biotransformation?

Answer 24