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Cell Proliferation and Survival Mechanisms Underlying Disease > Sulforaphane > Flashcards

Sulforaphane Flashcards

- What is sulforaphane - How does sulforaphane activate Nrf2 - Why is sulforaphane effective in so many animal models of human disease - What type of human disease sulforaphane is most likely to affect - The importance of the dose for optimal efficacy - The feasibility and challenges associated with translation of findings in animal models to humans

1
Q

What is sulforaphane

A
  • most potent naturally occuring dietary activator of nrf2
  • potent NQO1 inducer
  • isothiocyanate found in cruciferous vegetables (e.g. broccoli sprouts, cauliflower, kale, etc.)
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2
Q

How does sulforaphane activate Nrf2

A

by reacting with cysteines (mainly C151), inhibiting Keap1

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3
Q

Why is sulforaphane effective in so many animal models of human disease

A
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4
Q

How many genes can the Nrf2 pathway alter the gene expression of

A

affects expression of over 200 genes (including antioxidant and anti-inflammatory genes, and also any genes that inactivate harmful compounds)

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5
Q

explain the link between crucigerous vegetable consumption and cancer

A
  • reductions in all-cause mortality
  • reductions in prostate, bladder, breast, and lung (in smokers) cancer risks
  • increases survival in patients with bladder cancer
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6
Q

Effects of sulforaphane

A
  • potent cancer preventative effects
  • influence on cardiovascular disease
  • sulforaphane can help enhance the excretion of carcinogens
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7
Q

How is sulforaphane produced

A

hydrolytic conversion of glucoraphanin following ingestion of cruciferous vegetables (e.g. broccoli sprouts)

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8
Q

What are glucoinolates

A
  • a class of secondary compounds present in angiosperms of cruciales
  • functions as part of a defence mechanism against pathogens and insects
  • glucoraphanin is the precursor to sulforaphane
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9
Q

production of glucoinolates from methionine

A
  • conversion of methionine to aldoxime via activity of gene products
  • aldoxime undergoes conjugation with cysteine (acts as sulfur donor)
  • cleaved by C-S lyase
  • glucoinolate products are formed through detoxification
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10
Q

how is sulforaphane converted from glucoraphanin

A
  • isothiocyanates form glucoinolates through myrosinase
  • hydrolytic conversion occuring through cruciferous plant tissue damage (e.g. crushing, chopping, chewing)
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11
Q

mechanism by which sulforaphane can reduce cancer risk

A
  • deactivation of phase I biotransformation enzymes
  • prevent DNA adducts (type of DNA damage shown to lead to cancer)
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12
Q

Phase I biotransformation enzymes

A

the conversion of procarcinogens to active carcinogens

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13
Q

Sulforaphane metabolism

A
  • via mercapturic acid pathway
  • involves initial conjugation with glutathione
  • catalysed by GST enzymes
  • N-acetylation is important for sulforaphane excretion
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14
Q

Which GST isoforms have the greatest activity on sulforaphane

A

GST-M1 and GST-T1

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15
Q

null mutations

A

result in the absence of functional gene product

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16
Q

Explanation for conflicting studies on the genetic polymorphisms in GST isoforms and cancer risk

A
  • ethnic differences
  • small sample sizes
  • variability in study design
  • heterogeneity of cancer types: do GST polymorphisms have different effects?
  • interaction with environmental factors
17
Q

Chemopreventative activity of sulforaphane

A
  • has the capacity to inhibit the malignant transformation of various cell types and limit cancer progression following carcinogen exposure
18
Q

Phase II enzymes

A
  • responsible for mutagen elimination
  • deactivate pro-carcinogenic agents and transform them into less reactive, water soluble conjugates
19
Q

How does sulforaphane activate phase II detoxification enzymes

A
  • induce nuclear translocation of nrf2 via degradative loss of Keap1 via conformational changes
20
Q

How can sulforaphane limit the progression of tumour development

A
  • activation of apoptosis
  • NFkB pathway inhibition
  • cell cycle arrest induction
21
Q

How can sulforaphane induce apoptosis

A
  • via activation of several apoptotic pathways
  • activation of caspase-8 and caspase-9
  • downregulation of anti-apoptotic Bcl-2 and Bcl-XL gene
  • upregulation of pro-apoptotic Bax
  • proteolytic activation of caspase-3
  • degradation of PARP
22
Q

caspase-3

A
  • coordinates the desctruction of cellular structures (e.g. degradation of cytoskeletal proteins)
  • activity is tightly regulated
  • produced as inactive zymogens and undergo cascade of catalytic activation
23
Q

caspase-8

A
  • propagates apoptotic signal
  • directly cleaving and activating downstream caspases or by
  • cleaving BH3 Bcl-2 interacting protein, leading to release of cytochrome c
24
Q

caspase-9

A
  • initiates intrinsic pathway of apoptosis
25
Q

what is the initiating signal of sulforaphane-mediated apoptosis

A
  • formation of ROS
  • disruption of mitochrondrial membrane potential
  • cytosolic release of cytochrome c
26
Q

Role of NOQ1

A

prevents the degradation of tumour suppressor p53

27
Q

How sulforaphane prevents diabetes-induced aortic damage

A

upregulation of Nrf2 and its downstream antioxidants

28
Q

How sulforaphane protects the brain against hypoxic-ischemic injury

A

increased expression of Nrf2 and HO-1 (one of the downstream taraget genes) in the brain

29
Q

Sulforaphane effect on inflammation and lesion volume following spinal cord injury

A
  • activation of nuclear factor E2-related factor 2/ARE pathway
  • neuroprotective
30
Q

Explain the importance of the dose of sulforaphane

A
  • with increasing doses of sulforaphane, there are increased levels of NQO1
  • at higher doses of sulforaphane, the effect began to get smaller
  • if dose was increased further it becomes toxic
  • must be regulated

Cell Proliferation and Survival Mechanisms Underlying Disease (11 decks)

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