Phase I Reactions

Question 1

What is the substrate of CYP1A1 , CYP1A2 for phase I reaction

Answer 1

PAH, HCA, aflatoxin

Question 2

What are the inducers or transcription factor ligands of CYP1A1, CYP1A2

Answer 2

PAH, HCA, PCBs, dioxins, some flavonoids and phytochemicals

Question 3

what is the nuclear receptor of CYP1A1 and CYP1A2`

Answer 3

Aryl hydrocarbon receptor (AhR)

Question 4

what are the substrates of CYP2A,B,C,D

Answer 4

pharmaceuticals

Question 5

what are the inducers or transcription factor ligands of CYP2A,B,C,D

Answer 5

barbiturates, phenobarbital

Question 6

what is the nuclear receptor of CYP2A,B,C,D

Answer 6

constitutive androstane receptor (CAR)

Question 7

what are the substrates of CYP2E1

Answer 7

acetaminophen, alcohol, nitrosamines, aflatoxin

Question 8

what are the inducers of CYP2E1

Answer 8

ketones, ethanol/alcohol

Question 9

what is the nuclear receptor of CYP2E1

Answer 9

there are none

- protein stabilization mechanism

Question 10

what CYP subfamily makes up 60% of liver CYPs

Answer 10

CYP3A

Question 11

what are the substrates of CYP3A

Answer 11

endogenous steroids, pharmaceuticals

Question 12

what are inducers of CYP3A

Answer 12

anabolic steroids

Question 13

what is the nuclear receptor of CYP3A

Answer 13

steroid hormone xenobiotic receptor (SXR)

Question 14

what are inducers

Answer 14

xenobiotics that increase the expression of specific CYP genes

Question 15

what is the purpose of inducing CYP gene expression

Answer 15

ensures we have enough CYP enzyme to metabolize X

• decrease risk of X accumulation
• may increase cancer risk
• phase I reaction

Question 16

How do nuclear receptors of CYP work

Answer 16

they heterodimerize with other nuclear receptors to induce an infinite number of patterns of CYP gene expression

Question 17

Describe how some xenobiotics can be agonist or ligands for transcription factor

Answer 17

• they bind to them forming a complex
• can accelerate transcription downstream genes (inducing expression of CYPs)
• some can function as CYP inhibitors and decrease function of CYP

Question 18

What is PXR

Answer 18

pregnan X receptor

Question 19

where is pregnan X receptor found

Answer 19

predominantly in the nucleus

Question 20

how does pregnane X receptor work

Answer 20

forms a heterodimer and binds to PXRE sites in DNA

- increases transcription of genes

Question 21

Pregnane X receptor increases transcription of genes encoding what?

Answer 21

• phase 1 enzymes (CYP2C and CYP3A)

- phase 2 enzymes (UDP-glucoronoshl transferases and sulfotransferases

Question 22

what is CAR

Answer 22

constitutive andostane receptor

Question 23

where is CAR found

Answer 23

in the cytoplasm when phosphorylated

Question 24

nuclear translocation of CAR is regulated by what

Answer 24

by its dephospho rylation

- protein kinase C - dependent phosphorylation keeps CAR in cytoplasm

Question 25

what causes CAR dephosphorlation

Answer 25

bidding of X+CAR changes the structure of CAR and causes its dephosphorylation (allowing it into the nucleus)

Question 26

what is PPAR

Answer 26

peroxisome proliferator-activated receptor

Question 27

PPAR forms a heterodimer with?

Answer 27

ligand bound PPAR forms a heterodimer with RXR

Question 28

where are PPARs located

Answer 28

in the nucleus | - but can alter nucleocytoplasmic shuttling and sub cellular localization

Question 29

what is AhR

Answer 29

aryl hydrocarbon receptor

Question 30

where is AhR inactive

Answer 30

kept inactive in the cytoplasm bound to a complex of proteins

Question 31

what does X binding do to AhR

Answer 31

will release AhR from binding partners in cytosol and translocates to nucleus

Question 32

what happens once AhR is in nucleus

Answer 32

heterodimerizes with ARNT and binds to DNA at xenobiotic response elements

Question 33

describe interaction between PXR and AhR

Answer 33

PXR interacts with AhR suppressing its activity and preventing AhR binding to XRE

Question 34

what is NRF2

Answer 34

nuclear factor erythroid 2-related factor 2

Question 35

NRF2 is sequestered by what

Answer 35

NRF2 is sequestered in cytoplasm by its negative regulator keep-1

Question 36

NRF2 targets include

Answer 36

- phase 2 enzymes AhR antioxidant response components

Question 37

What is the function of Thoil/sulfhydryl group electron donors

Answer 37

electrophile xenobiotics accept electrons from KEAP1= transformational change that causes the dissociation of KEAP1 from NRF2

Question 38

describe the 3 mechanisms of interaction of AhR with NRF2

Answer 38

- stimulation of CYP1A1= generate some ROS and reactive X intermediates that can modify KEAP1 and release NRF2 in cytoplasm - transcriptional stimulation of NRF2 synthesis by AhR and AhR synthesis by NRF2 - cooperation of AhR and NRF2 in the regulation antioxidant proteins such as NQo1 and otherd

Question 39

describe protein stabilization of CYP2E1

Answer 39

prolonged or chronic exposure to ketones or alcohol results in protein stabilization of CYP2E1

Question 40

what does protein stabilization of CYP2E1 result in

Answer 40

prevents the degradation of CYP2E1 - pool of this protein increases - faster phase I reactions catalyses by CYP2E1

Question 41

what is the function of CYP2E1

Answer 41

degrades ketones/ketone bodies to prevent acidosis

Question 42

describe influence of protein deficiency on phase I metabolism

Answer 42

- less amino acids for protein production= less CYP enzymes

Question 43

low protein diet decreases what cancer

Answer 43

aflatoxin induced liver cancer

Question 44

describe influence of starvation and ketosis on phase I metabolism

Answer 44

increased CYP2E1 expression due to increased production of ketones - protein stabilization of CYP2E1

Question 45

describe influence of high fat diet and obesity on phase I metabolidm

Answer 45

- increased 1,2,3 families of CYP - increased bio activation of X (HCA,PAH) - increased cancer risk

Question 46

describe the influence of vitamin A on phase I metabolism

Answer 46

high vitamin A (retinol)= decreased CYP expression

Question 47

how does vitamin A decrease CYP expression

Answer 47

retinol is converted to retinoid acid which regulated epithelial cell differentiation - potential link between vitamin A and reduced cancer risk

Question 48

describe influence of Beta carotene on phase I metabolism

Answer 48

increased CYP1A1 and CYP1A2 | - negative outcome, more reactive intermediated produced in phase I

Question 49

describe the influence of vitamin B (thiamine) deficiency on phase I metabolism

Answer 49

increased CYP2E1

Question 50

describe the influence of vitamin C deficiency on phase I metabolism

Answer 50

decrease of various CYPs | - due to lower Fe status (which is required for P450)

Question 51

describe the influence of iron deficiency on phase I metabolism

Answer 51

decrease CYPs in extra hepatic tissues

Question 52

describe the influence of PAH and HCA on phase I metabolism

Answer 52

- bind AhR and induce CYP1A1 and CYP1A2 gene expression | - more bio activation and cancer risk

Question 53

describe the influence of phytochemical on phase I metabolism

Answer 53

- bind AhR and block induction of CYP1A1 and CYP1A2 caused by PAH, HCA, PCBs and dioxins

Question 54

describe the influence of ethanol (alcohol) on phase I metabolism

Answer 54

rapid stabilization of CYP2E1

Question 55

describe the influence of caffeine on phase I metabolsim

Answer 55

induces liver CYP1A2 but has negative association with liver cancer

Question 56

describe the influence of tobacco on phase I metabolism

Answer 56

increased CYP1A1 and CYP1A2 transcription and translation | CYP bio activation and cancer risk