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
Douglas B. Kell
Arch Toxicol (2010) 84:825–889
Received: 14 June 2010 / Accepted: 14 July 2010 /
Published online: 17 August 2010

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
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-jB 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 antioxidants)
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.

Keywords Antioxidants Apoptosis Atherosclerosis
Cell death Chelation Chemical toxicology Iron
Neurodegeneration Phlebotomy Polyphenols Sepsis
SIRS Stroke Systems biology Toxicity

Ab b-amyloid
AD Alzheimer’s disease
ALS Amyotrophic lateral sclerosis
(Lou Gehrig’s disease)
BSE Bovine spongiform encephalopathy
CJD Creutzfeldt-Jakob disease
CNS Central nervous system
EAE Experimental autoimmune
GBA Glucocerebrosidase
HD Huntington’s disease
Htt Huntingtin protein
MCMC Markov chain Monte Carlo
MIRIAM Minimum information requested in the
annotation of biochemical models
MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MS Multiple sclerosis
PD Parkinson’s disease
RNS(s) Reactive nitrogen species
ROS(s) Reactive oxygen species
SBML Systems biology markup language
D. B. Kell (&)
School of Chemistry and the Manchester Interdisciplinary
Biocentre, The University of Manchester,
Manchester M1 7DN, UK

DOI 10.1007/s00204-010-0577-x

The Author(s) 2010. This article is published with open access at

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