Arch Toxicol (2010) 84:825–889 DOI 10.1007/s00204-010-0577-x REVIEW 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 Douglas B. Kell Received: 14 June 2010 / Accepted: 14 July 2010 / Published online: 17 August 2010 Ó The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Exposure to a variety of toxins and/or infec- means that multiple interventions (e.g. of iron chelators tious agents leads to disease, degeneration and death, often plus antioxidants) are likely to prove most effective. A characterised by circumstances in which cells or tissues do variety of systems biology approaches, that I summarise, not merely die and cease to function but may be more or can predict both the mechanisms involved in these cell less entirely obliterated. It is then legitimate to ask the death pathways and the optimal sites of action for nutri- question as to whether, despite the many kinds of agent tional or pharmacological interventions. involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evi- Keywords Antioxidants Á Apoptosis Á Atherosclerosis Á dence that in a great many cases, one underlying mecha- Cell death Á Chelation Á Chemical toxicology Á Iron Á nism, providing major stresses of this type, entails Neurodegeneration Á Phlebotomy Á Polyphenols Á Sepsis Á continuing and autocatalytic production (based on positive SIRS Á Stroke Á Systems biology Á Toxicity feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell Abbreviations death via apoptosis (probably including via pathways Abb-amyloid induced by changes in the NF-jB system). While every AD Alzheimer’s disease pathway is in some sense connected to every other one, I ALS Amyotrophic lateral sclerosis highlight the literature evidence suggesting that the (Lou Gehrig’s disease) degenerative effects of many diseases and toxicological BSE Bovine spongiform encephalopathy insults converge on iron dysregulation. This highlights CJD Creutzfeldt-Jakob disease specifically the role of iron metabolism, and the detailed CNS Central nervous system speciation of iron, in chemical and other toxicology, and EAE Experimental autoimmune has significant implications for the use of iron chelating encephalomyelitis substances (probably in partnership with appropriate anti- GBA Glucocerebrosidase oxidants) as nutritional or therapeutic agents in inhibiting HD Huntington’s disease both the progression of these mainly degenerative diseases Htt Huntingtin protein and the sequelae of both chronic and acute toxin exposure. MCMC Markov chain Monte Carlo The complexity of biochemical networks, especially those MIRIAM Minimum information requested in the involving autocatalytic behaviour and positive feedbacks, annotation of biochemical models MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydro- pyridine D. B. Kell (&) MS Multiple sclerosis School of Chemistry and the Manchester Interdisciplinary PD Parkinson’s disease Biocentre, The University of Manchester, RNS(s) Reactive nitrogen species Manchester M1 7DN, UK e-mail: [email protected] ROS(s) Reactive oxygen species URL: http://dbkgroup.org/; http://twitter.com/dbkell SBML Systems biology markup language 123 826 Arch Toxicol (2010) 84:825–889 SBRML Systems biology results markup NO peroxy language nitrite SIRS Systemic inflammatory response mitochondria •- syndrome O2 Ferritin TCDD, ‘dioxin’ 2,3,7,8-tetrachlorodibenzo-p-dioxin TSEs Transmissible spongiform • hydroxyl encephalopathies Fe(III) OH radical 2,4-D 2,4-dichlorophenoxyacetic acid Haber-Weiss Fenton reaction 2,4,5-T 2,4,5-trichlorophenoxyacetic acid reaction Fe(II) H2O2 Introduction oxidases e.g. NADPH O 2 oxidase; As a transition metal that can exist in several valencies, and mitochondria that can bind up to six ligands, iron is an important compo- nent of industrial catalysts in the chemical industry (Hagen Fig. 1 The Haber-Weiss and Fenton reactions combine using poorly liganded iron in a catalytic cycle to produce the very damaging 2006), especially for redox reactions. Its catalysis of specific hydroxyl radical. Poorly liganded iron can also be liberated via the reactions requires rather exact architectures at the catalytic destruction of haem and other iron-containing substances. Peroxyni- centre, and indeed much of the art and science of catalyst trite anion (ONOO-) is produced by the reaction of superoxide and • production involves determining and synthesising them. nitric oxide (NO ) which when protonated (pH ca 6.5–6.8) decom- poses to OH• and NO Nearly half of all enzymes are metalloproteins (Waldron 2 et al. 2009), and iron is also of considerable importance in biology as a component of all kinds of metalloproteins further Fe(II) from iron-sulphur centres and other iron-con- (Andreini et al. 2008, 2009) from haemoglobin to cyto- taining compounds such as ferritin (Arosio et al. 2009), chromes, as well as in the directed evolution of novel enzyme thereby driving reaction (1) in an autocatalytic, runaway activities (Pordea and Ward 2008; Que and Tolman 2008; kind of reaction. This kind of phenomenon has the potential Turner 2009). When serving in enzymes, the iron is normally to overwhelm any kinds of attempts at repair, and inflam- safely liganded, and any reactions catalysed are usually mation and oxidative stress are the hallmarks of each of the fairly specific. However, as is widely recognised, iron can conditions I summarise. Related reactions include perox- also have a dark side (Kell 2009a), in that when it is not ynitrite production (from the reaction of NO and superoxide) properly liganded (Graf et al. 1984), and in the ferrous form, (Babior 2000; Beckman et al. 1990; Beckman and Koppenol it can react with hydrogen peroxide (produced by mito- 1996; Goldstein and Mere´nyi 2008; Koppenol et al. 1992; chondria (e.g. Brennan and Kantorow 2009; Fato et al. 2008; Murphy et al. 1998; Pacher et al. 2007; Pavlovic and Orrenius et al. 2007) or (per)oxidases (Bedard and Krause Santaniello 2007; Pryor and Squadrito 1995; Radi et al. 2001, 2007; Cave et al. 2006) via the Fenton reaction (Goldstein 2002; Rubbo and O’Donnell 2005; Rubbo et al. 2009; Smith et al. 1993; Kruszewski 2003; Toyokuni 2002; Wardman and et al. 1997b; Squadrito and Pryor 1998; Szabo 1996; Szabo´ Candeias 1996; Winterbourn 1995), leading to the very et al. 2007; Torreilles et al. 1999; White et al. 1994; Zimmet reactive and damaging hydroxyl radical (OH•) and Hare 2006). These can lead to nitrotyrosine (Beckman À 1996; Goldstein and Mere´nyi 2008; Herce-Pagliai et al. FeðIIÞþH2O2 ! FeðIIIÞþOH þ OH ð1Þ 1998) (a reaction catalysed by poorly liganded iron, Superoxide (also produced by mitochondria) can react Beckman et al. 1992), or nitro-fatty acid (Aslan et al. 2001; with ferric iron in the Haber-Weiss reaction (Kehrer 2000) to produce Fe(II) again, thereby effecting redox cycling of Some small molecules derived the iron (Fig. 1): from macromolecule oxidation À O2 þ FeðIIIÞ!O2 þ FeðIIÞð2Þ •DNA 8-OH-2’-deoxyguanosine Ascorbate (vitamin C) can also replace OÀ for reducing 2 • Proteins nitrotyrosine, methionine the Fe(III) to Fe(II) (Hershko and Weatherall 1988), as can sulphoxime other reducing agents, and indeed too low a redox poise • Lipids 4-hydroxy-non-2-enal leads to DNA damage (e.g. Li and Marba´n 2010; Seifried et al. 2007). Fig. 2 Some small molecules that are derived from the oxidative attack of hydroxyl and other radicals on cellular macromolecules and The hydroxyl radical is exceptionally reactive and dam- that can act as biomarkers of oxidative stress, including that mediated aging to cellular components, and, for instance, can liberate by iron 123 Arch Toxicol (2010) 84:825–889 827 O’Donnell and Freeman 2001) production or protein cys- relating urinary 8-OHdG levels to serum ferritin concen- teine nitrosylation (Lancaster 2008; Landino 2008; Vaz and trations are particularly striking, and I have digitised them Augusto 2008) that can provide a means of their detection (cf. Pettifer et al. 2009 for pointers to automated ways of downstream. Some of these are shown in Fig. 2. A key point doing this in the future) and replotted some of them in here is that despite the widespread and uncritical use of the Fig. 3. term ROS to describe any ‘Reactive Oxygen Species’, most Ferritin levels (a common measure of body iron stores) such as superoxide and peroxide are not terribly reactive, in are also widely associated with disease development/ contrast to the hydroxyl radical (and peroxynitrite) which is, severity/ poor outcomes (e.g. Alissa et al. 2007; Armand and unliganded iron is required for hydroxyl radical et al. 2007; Bartzokis et al. 2007; Braun et al. 2004; production in the Fenton reaction. Hence the focus on Bugianesi et al. 2004; Chen et al. 2006; Choi et al. 2005; unliganded iron rather than the more nebulous ROSs, albeit Double et al. 2000; Fargion et al. 2001; Ferna´ndez-Real that (su)peroxide is necessarily involved. et al. 2002; Ford and Cogswell 1999; Forouhi et al. 2007; Clearly the occurrence of these activities leads to the He et al. 2007; Hubel et al. 2004; Ishizaka et al. 2005; Jehn (more or less irreversible) formation of a variety of sub- et al. 2004, 2007; Kaur et al. 2007; Kiechl et al. 1997; Lee stances that can act as biomarkers of these activities (Kell et al. 2006f; Lim et al. 2001; Rayman et al. 2002; Rouault 2009a), and such oxidised compounds are represented by 2006; Salonen et al. 1992; Sheth and Brittenham 2000; both small and macro-molecules. For instance, 8-hydroxy- Tuomainen et al. 1998; Valenti et al. 2007; Wilson et al. 20-deoxyguanosine (8-OHdG) (ChEBI 40304) also referred 2003; You et al.