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3237922 
Journal Article 
Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples 
Kell, DB 
2010 
Yes 
Archives of Toxicology
ISSN: 0340-5761
EISSN: 1432-0738 
84 
11 
825-889 
WOS:000284420500002 
Exposure to a variety of toxins and/or infectious agents
leads to disease, degeneration and death, often characterised by circumstances in which cells or
tissues do not merely die and cease to function but may be more or less entirely obliterated. It
is then legitimate to ask the question as to whether, despite the many kinds of agent involved,
there may be at least some unifying mechanisms of such cell death and destruction. I summarise
the evidence that in a great many cases, one underlying mechanism, providing major stresses of
this type, entails continuing and autocatalytic production (based on positive feedback
mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to
cell death via apoptosis (probably including via pathways induced by changes in the NF-kappa B
system). While every pathway is in some sense connected to every other one, I highlight the
literature evidence suggesting that the degenerative effects of many diseases and toxicological
insults converge on iron dysregulation. This highlights specifically the role of iron metabolism,
and the detailed speciation of iron, in chemical and other toxicology, and has significant
implications for the use of iron chelating substances (probably in partnership with appropriate
anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these
mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The
complexity of biochemical networks, especially those involving autocatalytic behaviour and
positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants)
are likely to prove most effective. A variety of systems biology approaches, that I summarise,
can predict both the mechanisms involved in these cell death pathways and the optimal sites of
action for nutritional or pharmacological interventions. 
Antioxidants; Apoptosis; Atherosclerosis; Cell death; Chelation; Chemical toxicology; Iron; Neurodegeneration; Phlebotomy; Polyphenols; Sepsis; SIRS; Stroke; Systems biology; Toxicity