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NUTR 4510- Food, Tox, Nutrition > Phase I Reactions > Flashcards

Phase I Reactions Flashcards

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1
Q

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

A

PAH, HCA, aflatoxin

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2
Q

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

A

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

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3
Q

what is the nuclear receptor of CYP1A1 and CYP1A2`

A

Aryl hydrocarbon receptor (AhR)

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4
Q

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

A

pharmaceuticals

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5
Q

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

A

barbiturates, phenobarbital

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6
Q

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

A

constitutive androstane receptor (CAR)

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7
Q

what are the substrates of CYP2E1

A

acetaminophen, alcohol, nitrosamines, aflatoxin

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8
Q

what are the inducers of CYP2E1

A

ketones, ethanol/alcohol

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9
Q

what is the nuclear receptor of CYP2E1

A

there are none

- protein stabilization mechanism

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10
Q

what CYP subfamily makes up 60% of liver CYPs

A

CYP3A

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11
Q

what are the substrates of CYP3A

A

endogenous steroids, pharmaceuticals

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12
Q

what are inducers of CYP3A

A

anabolic steroids

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13
Q

what is the nuclear receptor of CYP3A

A

steroid hormone xenobiotic receptor (SXR)

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14
Q

what are inducers

A

xenobiotics that increase the expression of specific CYP genes

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15
Q

what is the purpose of inducing CYP gene expression

A

ensures we have enough CYP enzyme to metabolize X

  • decrease risk of X accumulation
  • may increase cancer risk
  • phase I reaction
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16
Q

How do nuclear receptors of CYP work

A

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

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17
Q

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

A
  • 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
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18
Q

What is PXR

A

pregnan X receptor

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19
Q

where is pregnan X receptor found

A

predominantly in the nucleus

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20
Q

how does pregnane X receptor work

A

forms a heterodimer and binds to PXRE sites in DNA

- increases transcription of genes

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21
Q

Pregnane X receptor increases transcription of genes encoding what?

A
  • phase 1 enzymes (CYP2C and CYP3A)

- phase 2 enzymes (UDP-glucoronoshl transferases and sulfotransferases

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22
Q

what is CAR

A

constitutive andostane receptor

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23
Q

where is CAR found

A

in the cytoplasm when phosphorylated

24
Q

nuclear translocation of CAR is regulated by what

A

by its dephospho rylation

- protein kinase C - dependent phosphorylation keeps CAR in cytoplasm

25
Q

what causes CAR dephosphorlation

A

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

26
Q

what is PPAR

A

peroxisome proliferator-activated receptor

27
Q

PPAR forms a heterodimer with?

A

ligand bound PPAR forms a heterodimer with RXR

28
Q

where are PPARs located

A

in the nucleus

- but can alter nucleocytoplasmic shuttling and sub cellular localization

29
Q

what is AhR

A

aryl hydrocarbon receptor

30
Q

where is AhR inactive

A

kept inactive in the cytoplasm bound to a complex of proteins

31
Q

what does X binding do to AhR

A

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

32
Q

what happens once AhR is in nucleus

A

heterodimerizes with ARNT and binds to DNA at xenobiotic response elements

33
Q

describe interaction between PXR and AhR

A

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

34
Q

what is NRF2

A

nuclear factor erythroid 2-related factor 2

35
Q

NRF2 is sequestered by what

A

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

36
Q

NRF2 targets include

A
  • phase 2 enzymes
    AhR
    antioxidant response components
37
Q

What is the function of Thoil/sulfhydryl group electron donors

A

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

38
Q

describe the 3 mechanisms of interaction of AhR with NRF2

A
  • 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
39
Q

describe protein stabilization of CYP2E1

A

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

40
Q

what does protein stabilization of CYP2E1 result in

A

prevents the degradation of CYP2E1

  • pool of this protein increases
  • faster phase I reactions catalyses by CYP2E1
41
Q

what is the function of CYP2E1

A

degrades ketones/ketone bodies to prevent acidosis

42
Q

describe influence of protein deficiency on phase I metabolism

A
  • less amino acids for protein production= less CYP enzymes
43
Q

low protein diet decreases what cancer

A

aflatoxin induced liver cancer

44
Q

describe influence of starvation and ketosis on phase I metabolism

A

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

45
Q

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

A
  • increased 1,2,3 families of CYP
  • increased bio activation of X (HCA,PAH)
  • increased cancer risk
46
Q

describe the influence of vitamin A on phase I metabolism

A

high vitamin A (retinol)= decreased CYP expression

47
Q

how does vitamin A decrease CYP expression

A

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

48
Q

describe influence of Beta carotene on phase I metabolism

A

increased CYP1A1 and CYP1A2

- negative outcome, more reactive intermediated produced in phase I

49
Q

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

A

increased CYP2E1

50
Q

describe the influence of vitamin C deficiency on phase I metabolism

A

decrease of various CYPs

- due to lower Fe status (which is required for P450)

51
Q

describe the influence of iron deficiency on phase I metabolism

A

decrease CYPs in extra hepatic tissues

52
Q

describe the influence of PAH and HCA on phase I metabolism

A
  • bind AhR and induce CYP1A1 and CYP1A2 gene expression

- more bio activation and cancer risk

53
Q

describe the influence of phytochemical on phase I metabolism

A
  • bind AhR and block induction of CYP1A1 and CYP1A2 caused by PAH, HCA, PCBs and dioxins
54
Q

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

A

rapid stabilization of CYP2E1

55
Q

describe the influence of caffeine on phase I metabolsim

A

induces liver CYP1A2 but has negative association with liver cancer

56
Q

describe the influence of tobacco on phase I metabolism

A

increased CYP1A1 and CYP1A2 transcription and translation

CYP bio activation and cancer risk

NUTR 4510- Food, Tox, Nutrition (5 decks)

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