Biotransformation III

Question 1

What does induction mean in relation to toxicology and metabolism?

Answer 1

induction in relation to enzyme activity is when 1 drug interacts with another will cause the metabolism of the second drug to speed up

Question 2

Why is induction a concern when it comes to drug-interactions in the body?

Answer 2

1. alter the efficacy of a therapeutic agent
2. alter the toxicity of drugs or environmental chemicals

Question 3

why are drugs with a narrow therapeutic index especially concerned with induction and inhibition

Answer 3

because they don’t have as much flexibility when it comes to the toxic and therapeutic range, even a little bit outside of the index can be deadly

Question 4

What are some strong drug-metabolizing inducers

Answer 4

“TCDD” tetrachloridibenzodioxin (environmental toxin)
indol carbazole (found in cabbage family)

benzopyrene (found in cigarette smoke)

Question 5

What is special about benzo[a]pyrene for metabolism

Answer 5

in the body, benzo[a]pyrene will activate AHR and set off its own biotransformation

Question 6

explain the biotransformation of TCDD from its entrance to the body and its metabolism journey

Answer 6

TCDD is very lipophilic so it enters membranes readily
2. After it enters the membrane, it will attach to a protein complex with accessory proteins
3.once it is attached, it will go to the nucleus where it will now attach to ARNT, a protein involved in signalling AHR
4. it can bio transform by CYP1A1 which is involved in lung cancer

Question 7

explain how hyperforin, compound present in st.john’s warts leads to a reduction in efficacy of HIV medication

Answer 7

Hyperforin is an active ingredient in ST. John’s warts medication and when it is brought to the nucleus, it increases enzyme activity of CYP3A4, that metabolizes HIV drugs

Question 8

list a therapeutic benefit of induction of drug metabolism

Answer 8

in patients with neonate hyperbilirubin (jaundice)

The recommended treatment is phenobarbital because it increases the metabolism of bilirubin from body by inducing UDP-glucoronosyl transferase and elevating rate of glucuronidation/enzyme process metabolizing bilirubin

Question 9

What benefit does induction of CYP1A2 in liver have for high risk breast cancer patients

Answer 9

oral dose of indole-3-carbinol that induces CYP1A2 which will bio transform into estrogen and induce metabolism of 17 beta estradiol (estrogen)

Question 10

Describe the metabolism process of estradiol to estrogens

Answer 10

when 13C goes to the body, orally it will attach to AHR and it will cause 17 beta estradiol to hopefully bio transform via CYP1A2 and create 2OH and opt CYP1B1 which is carcinogenic

Question 11

why was seldane pulled from shelves

Answer 11

it was pulled after some patients had died and this was due to terfenadine in the drug being a cardiac poison and when it is not biotransformed into something less dangerous before entering the circulatory system, it will lead to arryhthmia deaths

Question 12

how do Pharma companies figure out which human enzymes will metabolize a particular drug

Answer 12

done via in vitro tests with human tissues by a three step process

1. pure enzyme expression
2. correlation analysis in human liver microsome bank from a bunch of donors
3. inhibition of selective enzymes with selective antibodies

Question 13

why wouldn’t Pharma companies want CYP3A4 as the primary enzyme for drug metabolism

Answer 13

because it already metabolizes so many other drugs

high variability and other drug interactions may inhibit/induce CYP3A4 activity

Question 14

why wouldn’t Pharma companies want CYP2D6 as the primary enzyme for metabolism

Answer 14

high degree of genetic polymorphism which may lead to some individuals being rapid/slow metabolizers