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
What is sulforaphane
- most potent naturally occuring dietary activator of nrf2
- potent NQO1 inducer
- isothiocyanate found in cruciferous vegetables (e.g. broccoli sprouts, cauliflower, kale, etc.)
How does sulforaphane activate Nrf2
by reacting with cysteines (mainly C151), inhibiting Keap1
Why is sulforaphane effective in so many animal models of human disease
How many genes can the Nrf2 pathway alter the gene expression of
affects expression of over 200 genes (including antioxidant and anti-inflammatory genes, and also any genes that inactivate harmful compounds)
explain the link between crucigerous vegetable consumption and cancer
- reductions in all-cause mortality
- reductions in prostate, bladder, breast, and lung (in smokers) cancer risks
- increases survival in patients with bladder cancer
Effects of sulforaphane
- potent cancer preventative effects
- influence on cardiovascular disease
- sulforaphane can help enhance the excretion of carcinogens
How is sulforaphane produced
hydrolytic conversion of glucoraphanin following ingestion of cruciferous vegetables (e.g. broccoli sprouts)
What are glucoinolates
- 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
production of glucoinolates from methionine
- 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
how is sulforaphane converted from glucoraphanin
- isothiocyanates form glucoinolates through myrosinase
- hydrolytic conversion occuring through cruciferous plant tissue damage (e.g. crushing, chopping, chewing)
mechanism by which sulforaphane can reduce cancer risk
- deactivation of phase I biotransformation enzymes
- prevent DNA adducts (type of DNA damage shown to lead to cancer)
Phase I biotransformation enzymes
the conversion of procarcinogens to active carcinogens
Sulforaphane metabolism
- via mercapturic acid pathway
- involves initial conjugation with glutathione
- catalysed by GST enzymes
- N-acetylation is important for sulforaphane excretion
Which GST isoforms have the greatest activity on sulforaphane
GST-M1 and GST-T1
null mutations
result in the absence of functional gene product
Explanation for conflicting studies on the genetic polymorphisms in GST isoforms and cancer risk
- ethnic differences
- small sample sizes
- variability in study design
- heterogeneity of cancer types: do GST polymorphisms have different effects?
- interaction with environmental factors
Chemopreventative activity of sulforaphane
- has the capacity to inhibit the malignant transformation of various cell types and limit cancer progression following carcinogen exposure
Phase II enzymes
- responsible for mutagen elimination
- deactivate pro-carcinogenic agents and transform them into less reactive, water soluble conjugates
How does sulforaphane activate phase II detoxification enzymes
- induce nuclear translocation of nrf2 via degradative loss of Keap1 via conformational changes
How can sulforaphane limit the progression of tumour development
- activation of apoptosis
- NFkB pathway inhibition
- cell cycle arrest induction
How can sulforaphane induce apoptosis
- 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
caspase-3
- 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
caspase-8
- propagates apoptotic signal
- directly cleaving and activating downstream caspases or by
- cleaving BH3 Bcl-2 interacting protein, leading to release of cytochrome c
caspase-9
- initiates intrinsic pathway of apoptosis
what is the initiating signal of sulforaphane-mediated apoptosis
- formation of ROS
- disruption of mitochrondrial membrane potential
- cytosolic release of cytochrome c
Role of NOQ1
prevents the degradation of tumour suppressor p53
How sulforaphane prevents diabetes-induced aortic damage
upregulation of Nrf2 and its downstream antioxidants
How sulforaphane protects the brain against hypoxic-ischemic injury
increased expression of Nrf2 and HO-1 (one of the downstream taraget genes) in the brain
Sulforaphane effect on inflammation and lesion volume following spinal cord injury
- activation of nuclear factor E2-related factor 2/ARE pathway
- neuroprotective
Explain the importance of the dose of sulforaphane
- 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
