Phase I Reactions Flashcards
What is the substrate of CYP1A1 , CYP1A2 for phase I reaction
PAH, HCA, aflatoxin
What are the inducers or transcription factor ligands of CYP1A1, CYP1A2
PAH, HCA, PCBs, dioxins, some flavonoids and phytochemicals
what is the nuclear receptor of CYP1A1 and CYP1A2`
Aryl hydrocarbon receptor (AhR)
what are the substrates of CYP2A,B,C,D
pharmaceuticals
what are the inducers or transcription factor ligands of CYP2A,B,C,D
barbiturates, phenobarbital
what is the nuclear receptor of CYP2A,B,C,D
constitutive androstane receptor (CAR)
what are the substrates of CYP2E1
acetaminophen, alcohol, nitrosamines, aflatoxin
what are the inducers of CYP2E1
ketones, ethanol/alcohol
what is the nuclear receptor of CYP2E1
there are none
- protein stabilization mechanism
what CYP subfamily makes up 60% of liver CYPs
CYP3A
what are the substrates of CYP3A
endogenous steroids, pharmaceuticals
what are inducers of CYP3A
anabolic steroids
what is the nuclear receptor of CYP3A
steroid hormone xenobiotic receptor (SXR)
what are inducers
xenobiotics that increase the expression of specific CYP genes
what is the purpose of inducing CYP gene expression
ensures we have enough CYP enzyme to metabolize X
- decrease risk of X accumulation
- may increase cancer risk
- phase I reaction
How do nuclear receptors of CYP work
they heterodimerize with other nuclear receptors to induce an infinite number of patterns of CYP gene expression
Describe how some xenobiotics can be agonist or ligands for transcription factor
- 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
What is PXR
pregnan X receptor
where is pregnan X receptor found
predominantly in the nucleus
how does pregnane X receptor work
forms a heterodimer and binds to PXRE sites in DNA
- increases transcription of genes
Pregnane X receptor increases transcription of genes encoding what?
- phase 1 enzymes (CYP2C and CYP3A)
- phase 2 enzymes (UDP-glucoronoshl transferases and sulfotransferases
what is CAR
constitutive andostane receptor
where is CAR found
in the cytoplasm when phosphorylated
nuclear translocation of CAR is regulated by what
by its dephospho rylation
- protein kinase C - dependent phosphorylation keeps CAR in cytoplasm
what causes CAR dephosphorlation
bidding of X+CAR changes the structure of CAR and causes its dephosphorylation (allowing it into the nucleus)
what is PPAR
peroxisome proliferator-activated receptor
PPAR forms a heterodimer with?
ligand bound PPAR forms a heterodimer with RXR
where are PPARs located
in the nucleus
- but can alter nucleocytoplasmic shuttling and sub cellular localization
what is AhR
aryl hydrocarbon receptor
where is AhR inactive
kept inactive in the cytoplasm bound to a complex of proteins
what does X binding do to AhR
will release AhR from binding partners in cytosol and translocates to nucleus
what happens once AhR is in nucleus
heterodimerizes with ARNT and binds to DNA at xenobiotic response elements
describe interaction between PXR and AhR
PXR interacts with AhR suppressing its activity and preventing AhR binding to XRE
what is NRF2
nuclear factor erythroid 2-related factor 2
NRF2 is sequestered by what
NRF2 is sequestered in cytoplasm by its negative regulator keep-1
NRF2 targets include
- phase 2 enzymes
AhR
antioxidant response components
What is the function of Thoil/sulfhydryl group electron donors
electrophile xenobiotics accept electrons from KEAP1= transformational change that causes the dissociation of KEAP1 from NRF2
describe the 3 mechanisms of interaction of AhR with NRF2
- 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
describe protein stabilization of CYP2E1
prolonged or chronic exposure to ketones or alcohol results in protein stabilization of CYP2E1
what does protein stabilization of CYP2E1 result in
prevents the degradation of CYP2E1
- pool of this protein increases
- faster phase I reactions catalyses by CYP2E1
what is the function of CYP2E1
degrades ketones/ketone bodies to prevent acidosis
describe influence of protein deficiency on phase I metabolism
- less amino acids for protein production= less CYP enzymes
low protein diet decreases what cancer
aflatoxin induced liver cancer
describe influence of starvation and ketosis on phase I metabolism
increased CYP2E1 expression due to increased production of ketones
- protein stabilization of CYP2E1
describe influence of high fat diet and obesity on phase I metabolidm
- increased 1,2,3 families of CYP
- increased bio activation of X (HCA,PAH)
- increased cancer risk
describe the influence of vitamin A on phase I metabolism
high vitamin A (retinol)= decreased CYP expression
how does vitamin A decrease CYP expression
retinol is converted to retinoid acid which regulated epithelial cell differentiation
- potential link between vitamin A and reduced cancer risk
describe influence of Beta carotene on phase I metabolism
increased CYP1A1 and CYP1A2
- negative outcome, more reactive intermediated produced in phase I
describe the influence of vitamin B (thiamine) deficiency on phase I metabolism
increased CYP2E1
describe the influence of vitamin C deficiency on phase I metabolism
decrease of various CYPs
- due to lower Fe status (which is required for P450)
describe the influence of iron deficiency on phase I metabolism
decrease CYPs in extra hepatic tissues
describe the influence of PAH and HCA on phase I metabolism
- bind AhR and induce CYP1A1 and CYP1A2 gene expression
- more bio activation and cancer risk
describe the influence of phytochemical on phase I metabolism
- bind AhR and block induction of CYP1A1 and CYP1A2 caused by PAH, HCA, PCBs and dioxins
describe the influence of ethanol (alcohol) on phase I metabolism
rapid stabilization of CYP2E1
describe the influence of caffeine on phase I metabolsim
induces liver CYP1A2 but has negative association with liver cancer
describe the influence of tobacco on phase I metabolism
increased CYP1A1 and CYP1A2 transcription and translation
CYP bio activation and cancer risk
