J7ournal ofNeurology, Neurosurgery, and Psychiatry 1993;56:943-946

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NEUROLOGYNEUROSURGERY& PSYCHIATRY

Editorial

Hypersusceptibility to chemicals: risk factors for neurologicaldisease?

Neurotoxicology has taken on a new lease of life as itbecomes clear that chemicals may be responsible formore than the occasional epidemic caused by unusuallyhigh exposure to a dietary toxin, such as lathyrism andcassava poisoning, or from industrial accident, substanceabuse or the pharmaceutical industry. The role of theclinician in recognising unusual cases and clusters wherethere is a clue to the chemical trigger cannot beover-emphasised. Easily dismissed coincidences, can beimportant because they may establish the relevance ofcurrent hypotheses or even generate new ones. TheN-methyl-4-phenyl tetrahydropyridine (MPTP) andDomoic acid outbreaks of neurotoxin mediated damageare recent examples of this.'-3The interaction between chemical exposure and genet-

ically determined hypersusceptibility may be crucial tounderstanding a number of poorly understood neuro-logical diseases and is worthy of further consideration.

The importance ofdoseParacelsus (1493-1541), who first expressed views thatremain the basis of the science of toxicology,4 emphasisedthe toxic agent as a chemical entity and antedated PaulEhrlich's 'Magic Bullet' in proposing a degree of speci-ficity for both therapeutic and toxic effects. Paracelsusconsidered that nearly all substances were potential poi-sons and that the difference between a therapeutic ortoxic response was often the dosage. Argument continuesabout whether certain natural chemicals are toxins with-out understanding that the dose in the vicinity of the tar-get cell or subcellular organelle may be crucial. Recentreminders are glutamate and related compounds, toxic atcertain concentrations and locations, but vital neuro-transmitters at others. Discussion of the potential toxicityof dopamine sometimes has the same basic flaws.4Conversely chemicals may be toxic in cell culture or inanimal experiments but only at doses that would not bereached in vivo.

Neurotoxins: specificity and mechanism ofneuronal damageNatural (and synthetic) toxins have been used extensivelyas tools in helping to understand the workings of thenervous system, such as, the studies on strychnine,emetine and carbon monoxide by Magendie and hispupil Claude Bernard. Later studies on botulinus,

tetanus and spider toxins were landmarks and demon-strate the specific dysfunction of certain neurons after aparticular exposure sometimes due to a single biochemi-cal lesion. Claude Bernard's treatise on ExperimentalMedicine6 was essentially a toxicology thesis and thewhole concept of homeostasis and the "milieu interior"re-emphasises that many compounds are toxic once theystray outside physiological limits.

In recent years there has been intense interest in inves-tigating the biochemical mechanisms of cell death in sub-populations of neurons, in both the peripheral andcentral nervous system, after a variety of insults. Theseinclude the disruption of brain energy metabolism andthe failure of adequate ATP synthesis by cutting off thesupply of nutrients. More recently there has been interestin intraneuronal calcium homeostasis, production andquenching of oxygen and other toxic radicals, the effectof inhibition of the mitochondrial electron transportchain, activation of proteolytic pathways and excitotoxicdamage.Y"3 These and other mechanisms are often inter-related producing a cascade of biochemical events.Future therapeutic options to rescue cells may depend onintervening before a hypothetical point of no return isreached. Separating early from late biochemical changeson diseased tissue can be difficult, even before ante- andpost-mortem artefacts are addressed. Distinguishing thecatastrophic biochemical changes of death from factorswithin the cell that may have predisposed to their prema-ture demise is fraught with problems.

Selective neuronal deathIn 1937 Vogt and Vogt'4 expounded the important con-cept of selective neuronal death recognising that thebrain was capable of reacting to generalised forms oftrauma, such as hypoxia, in a non-uniform manner andsuggested that specific instrinsic properties of certainnerve cells were responsible for their selective vulnerabil-ity. "Pathoclisis", which largely replaced previous theo-ries, related to the degree of vascularity. Initiallydifferential energy failure was thought to be responsibleuntil it was realised that incomplete ischaemia couldcause more cell loss than complete ischaemia. In theearly 80's the role of synaptic transmission was investi-gated and it was subsequently shown that innervation byexcitatory amino acid neuronal systems'5 16 (glutamatewas already known to have toxic potential'7) was the keyelement in a vulnerability to hypoxia, convulsions and

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hypoglycaemia. Thus the excitotoxic hypothesis wasborn. Other mechanisms that include differences inactive transport and channelling systems that concentratethe toxin will be important, as may differences in mito-chondrial function and free radical defence mechanisms,and a whole host of other factors that will emerge toexplain selective vulnerability amongst subpopulations ofneurons or glia exposed to particular stresses.

Xenobiotics-exposure, safety margins, delayedeffects and hypersusceptibilityPercival Pott (1775) is credited with the role of xenobi-otics (foreign chemicals) in human disease. Although ill-ness due to hypersusceptibility to the fava bean (nowknown to be secondary to defective glucose-6-phosphatedehydrogenase) was known at the time of Pythagoras.There are many other examples of "ecogenetic" diseaseswhereby inheritance of an unusual protein leads toextreme sensitivity to an environmentally derived chemi-cal trigger, for example, a,antitrypsin deficiency, malig-nant hyperpyrexia, suxamethonium apnoea and otherpharmacogenetic disorders. The role of xenobiotics inprecipitating migraine has been known from ancienttimes and still remains a common and notable exampleof an acute idiosyncratic response to chemicals found inour diet. Pott's main contribution was recognising thatsuch xenobiotic exposure could result in a long latencyillness such as cancer. Slow poisoning of a nervoussystem that regenerates with difficulty and has largefunctional reserves could quite easily lead to the lateonset of clinical illness even though the process hadbeen active over decades; this lack of close temporal rela-tionship leads to difficulties in recognition of a causalassociation.The number of xenobiotics in our environment is

enormous but rarely has toxicity, particularly long term,been adequately tested.18 Testing remains difficult asmany xenobiotics are not toxic in their own right but aresubstrates for the formation of endogenous toxins andthus are protoxins. Animal experimentation has beenused for detecting adverse responses and much usefulinformation has been obtained. The problem has been inassessing their relevance for humans and that extrapola-tion of such experimental findings is not an easy exerciseeven on the rare occasions when the biological mecha-nisms involved are understood. The idea of safety limitsto exposure is however flawed when it ignores long termeffects or the likelihood of the rare hypersusceptibleindividual.

Xenobiotic metabolismBiotransformation of virtually all xenobiotics that areabsorbed occur rapidly, chiefly in the liver during firstpass metabolism and often differs dramatically, bothquantitatively and qualitatively between individuals.'921Absorption requires a degree of lipid solubility whereasexcretion via the biliary tract or kidney requires a morepolar water soluble compound. Normally the first step isan oxidation reaction, often by Cytochrome P450, andlargely occurs in the liver and the second a conjugation.Usually these steps reduce the biological half life enor-mously but they should not be thought of as simpledetoxification reactions for two reasons. Firstly, the com-partment in which the reaction takes place can be impor-tant, such as, on which side of the blood-brain barrier orin which subcellular compartment; toxins can get trappedjust where you do not want them. Secondly, the oxida-

tion step, or more rarely conjugation can produce a toxicmetabolite.The term "lethal synthesis" was first used by Peters in

1952 in his Croonian lecture22 for describing the transfor-mation of fluoroacetic acid within CNS tissue to the toxicfluorocitric acid. Many other reactions will take place,not as in this case in the tissue in which the damageoccurs, but sometimes distantly by the xenobioticmetabolising enzymes, of which the cytochrome P450superfamily of enzymes is the best known.2' These phe-nomena are by no means unique to xenobiotics and it isequally possible that lethal synthesis can take place fromendogeneous substrates. Despite some caveats,Cytochrome P450 and other xenobiotic enzymes systemsare an important defence mechanism to cope with ourvaried and changing chemical environment and is likelyto have been an important evolutionary step as theenzymic machinery seems to be able to cope with anextremely wide range of substrates, including new chal-lenges, and in some instances is inducible which hasobvious adaptive significance.24 The evidence is in favourof this complex system being tuned to cope with mostenvironmental chemical hazards that produce acute andlife threatening dangers but may not be so efficient inprotecting neurons or avoiding mutagens particularly asthe effect may not occur until after the age of biologicalusefulness.

Slow and fast metabolisers of xenobiotics are welldescribed particularly from studies on isoniazid anddebrisoquine (in both instances the slow metaboliser isassociated with neuropathy after exposure to isoniazidand perhexiline respectively). Pharmacogenetics hasshown that much of this variation is genetically deter-mined,25 27 with many other polymorphisms alreadydescribed, for example, for monoamine oxidase B andthiol methyl transferase.2829 It is equally clear that envi-ronmental influences have an effect on enzymic function,most dramatically when there is an increase in enzymeactivity after exposure to the relevant substrate or when itis induced or repressed by drugs such as phenobarbitoneor cimetidine.

Hypersusceptibility may reside in variation in thehandling ofxenobioticsThe stresses that a neuron may find itself under may besubject to enormous individual variation and not justrelated to the degree of environmental exposure.Susceptibility may lie at the level of the cell destined todie and could include genetically determined or acquireddefects in any of the defence systems involved in themechanisms of cell death already alluded to, for example,mitochondrial, antioxidant and cellular buffering func-tions. The recent discovery of mutations in one of thesuperoxide dismutase gene in familial motor neuron dis-ease is a dramatic example of this phenomenon.'0 Thereis, however, considerable evidence that in some caseshypersensitivity to chemical injury resides in thoseenzymes involved in the initial metabolism of the com-pound that influence the dose of toxin delivered to thecell. This arena is now a growth industry in general toxi-cology. A rapidly increasing number of such genetic traitsare being identified and becoming linked with diseasestates, particularly cancer,3 and all carry the liability of ahigher susceptibility to chemical injury. It is also probablethat physiological regulatory systems including thecytokine network and the immune system will be foundto modify the expression of chemically induced toxicitywith interindividual variations in response. Genetic fac-tors may also determine the chemical environment that

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the individual seeks. Xenobiotic enzyme systems areactive in olfactory tissue32 which may provide a feedbackmechanism signalling to the individual which compoundssuit their particular metabolism. Dysfunction and thendestruction of the olfactory pathway, as in several neuro-degenerative diseases, may influence this relationship andcause a vicious cycle of increasingly inappropriateexposure.The MPTP story has taught us that a chemical is

capable of causing such selective neuronal death that itcan mimic Parkinson's disease. Since there is so muchoverlap with other degenerative diseases of the nervoussystem, chemicals could cause others similar disorders. Itwas only a series of serendipitous steps that led to theuncovering of MPTP-like neurotoxins. If chemicals cancause such damage it is a plausible logical progression tosuggest that individual susceptibility may reside in eithera failure to detoxify neurotoxins or that lethal synthesis oftoxins can take place in certain individuals. Migraine andsome diet- or drug-sensitive neurobehavioural diseasesare obvious candidate examples of acute conditions butmounting evidence suggests that delayed toxicity in thehypersusceptible individual could be responsible forsome neurodegenerative disorders.

Evidence to date in neurodegenerative diseaseDefective xenobiotic enzymes may be a significant riskfactor for the development of Parkinson's disease, anexacerbating element, and one that influences drugresponsiveness and side effects. For instance, althoughphenotypic studies were unimpressive the poormetaboliser debrisoquine genotype is over-represented, atleast in hospital based populations of Parkinson'sdisease."3 34 It also appears that N-methylated pyridinesnot too distantly related to MPTP-like compounds, areexcreted in high concentration in patients withParkinson's disease'5 and this increased production, ordecreased catabolism that may involve cytochrome P450,could lead to a rise in compounds potentially toxic todopaminergic neurons. There may also be alterations infunction of monoamine oxidase B (MAO-B) inParkinson's disease36 37 which could be of importanceas MAO-B converts the protoxin MPTP to the toxinMPP+ 38 and that blockade of this enzyme may retard theprogress of the disease.39 Thus a series of largely geneti-cally determined alterations in enzymic function couldact alone or in concert to produce a biochemicalendophenotype that, if provoked by an environmentallyderived chemical trigger, is hostile to the substantia nigrain the long term. The recent evidence that fetal implantsdo rather better in MPTP Parkinsonism than inParkinson's disease40 is compatible with this as in the lat-ter case exposure to the putative toxic atmosphere per-sists.

Decreased activity of the enzyme cysteine dioxygenasein Parkinson's, motor neuron and Alzheimer's diseaseshas also been found4' 42; this raises the level of the excito-toxin cysteine and simultaneously decreases sulphateavailability,43 which is important for several detoxificationsteps. Although this finding is not specific for any onedisease it may represent a necessary biochemical compo-nent for damage to occur or relate to disease severity; thismirrors many other findings in the neurodegenerativediseases where a mix of specific and non-specific changesis found, emphasising the overlap between them. Diseasespecific abnormalities that may relate to mechanisms ofselective neuronal death rather than severity are adecreased acetylation capacity" and altered capacity tomethylate sulphur compounds in motor neuron and

Parkinson's disease. The latter is due to differences inactivity of thiol methyl transferase45 best known for itsrole in detoxification of hydrogen sulphide, which may bedeficient in Parkinson's disease. This enzyme is alsoknown to methylate mercury to more toxic derivativeswhich may be a factor in motor neuron disease where theenzyme is overactive. Potentially the sulphur equivalentof the N-methylated pyridines could be produced fromother substrates though nothing as yet is known aboutthe toxicity of such substances or whether or not they arepreferentially concentrated in motor neurons in a similarway that MPP + is avidly taken up by the dopaminetransporter.

The potentialIf this hypothesis about the importance of hypersuscepti-bility to chemical factors is true, we have an interestingand hopefully remediable interaction between geneticallydetermined traits that act as an Achilles' heel if exposedto some crucial chemical stress. Such individuals could inturn be identifiable and technological advances will makethis a testable and refinable proposition. Enzymicmachinery may then be modified towards greater safetyand the pharmaceutical industry should explore thesepossibilities, alternatively critical environmental toxins orprotoxins could be avoided by a preemptive manipulationof diet. A new dawn of preventive approaches towardssome neurological diseases will be an exciting prospect.Identifying the environment trigger may not be easy.However, once we know the chief metabolic pathways,we will be able to make an educated guess as to the likelysubstrates. The proposed culprits may then be sought inepidemiological studies which would have greater poweras sub-populations of the disease groups could then beidentified. In the 'good' metaboliser group the accumula-tive environmental dosage would have to be greater andso more prominent in a combined biochemical/epidemio-logical survey.

University Department of Clinical Neurology,Queen Elizabeth Hospital,Edgbaston, Birmingham B15 2TH, UK

ADRIAN WILLIAMS

1 Langston JW, Ballard P, Tetrud JW & Irwin I. Chronic Parkinsonism inhumans due to a product of meperidine-analog synthesis. Science NY1983;219:979-80.

2 Davis GC, Williams AC, Markey SP, et al. Chronic Parkinsonism sec-ondary to intravenous injection of Meperidine analogues. Psych Res1979;1:249.

3 Teitelbaum JS, Zatorre RJ, Carpenter S, et al. Neurologic sequelae ofDomoic acid intoxication due to the ingestion of contaminated mussels.NEngJMed 1990;322:1781-7.

4 Pagel W: Paracelsus: An introduction to philosophical medicine in the era of theRenaissance. New York: S Karger, 1958.

5 Olanow CW. Oxidation reactions in Parkinson's disease. Neurology1990;40(Suppl 3):32-7.

6 Bernard C. An introduction to the study of experimental medicine, NewYork, H Schuman, trans by H C Greene. 1949.

7 Choi DW. Glutamate neurotoxicity and diseases of the neurons system.Neuron 1988;1:623-34.

8 Kontos HA. Oxygen radicals in CNS damage. Chem Biol Interact 1989;72:229-55.

9 Sies;o BK. Calcium in the brain under physiological and pathological con-ditions. Eur Neurol 1990;30(Suppl 2):3-9.

10 Halliwell B, Gutteridge JMC, Cross CE. Free radicals, antioxidants andhuman disease: Where are we now? J Lab Clin Med 1992;119:598-620.

11 Krieglstein J, Nuglisch J. Metabolic disorders as consequences of drug-induced energy deficits. In: Herken H, Hucho F, eds. Selective Neuro-toxicity. New York: Springer-Verlag: 1992; 111-39.

12 Heikkila RE, Nicklas WI, Vyas I, Duvoisin RC. Dopaminergic toxicity ofrotenone and the 1-methyl-4-phenylpyridinium ion after their sterotaxicadministration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci Lett 1985;62:389-94.

13 Schapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P, MarsdenCD. Motochondrial complex I deficiency in Parkinson's disease.J Neurochem 1990;54:823-7.

14 Vogt C, Vogt 0. Sitz und Wesen der Krankheiten im Lichte der topistis-chen Hirnforschung und des Variierens der Tiere. J Psychol Neurol1937;47:237-457.

15 Rothman SM. Synaptic activity mediates death of hypoxic neurons.Science 1983;220:536-7.

945

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Editonial

16 Rothman SM. Synaptic release of excitatory amino acid neurotransmittermediates anoxic neuronal death. Biochem Pharmacol 1984;4: 1884-91.

17 Olney W. Brain lesion, obesity and other disturbances in mice treatedwith monosodium glutamate. Science 1969;164:719-21.

18 Albert A. Xenobiosis. Food, drugs and poisons in the human body.London: Chapman and Hall, 1987.

19 Williams RT. Detoxification mechanisms, 2nd ed. New York, Wiley andSons, 1959.

20 Jenner P, Testa B (eds). Concepts in Drug Metabolism. New York; MarcelDekker, 1980.

21 Klaasen CD, Rozman K. Adsorption, distribution and excretion of toxi-cants. In: Amdur MO, Doull J, Klaasen CD, eds. Toxicology, the basicscience ofpoisons 4th ed. New York: Pergamon Press, 1991;50-87.

22 Peters RA. Lethal synthesis (Croonian lecture). Proc R Soc Lond (Biol)1952;139: 10-170.

23 Gonzalez FJ. The molecular biology of cytochrome P450s. Pharmacol Rev1988;40:243.

24 Nebert DW, Jaiswal AK, Meyer UA, Gonzalez FJ. Human P-450 genes:evolution, regulation and possible role in carcinogenesis. Biochem SocTrans 1988;15:586-9.

25 Motulsky AG. Pharmacogenetics. Prog Med Genet 1964;3:49.26 Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic

hydroxylation of debrisoquine in man. Lancet 1977;ii:584-6.27 Weber WW, Hein DW. N-Acetylation pharmacogenetics. Pharmacol Rev

1985;37:25.28 Konradi C, Ozelius L, Breakefield XO. Highly polymorphic (GT). repeat

sequence in Intron II of the human MAOB gene. Genomics, 1992;12:176-7.

29 Price RA, Keith RA, Spielman RS. Major gene polymorphism for humanerythrocyte thiol methyl transferase. Genet Epidemiol 1989;6:651-62.

30 Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn super-oxide dismutase gene are associated with familial amyotrophic lateralsclerosis. Nature 1993;362:59-62.

31 Bock KW. Metabolic polymorphisms affecting activation of toxic andmutagenic arylamines. TIPS 1992;13:223-6.

32 Ding X, Coon MJ. Purification and characterization of two unique formsof cytochrome P-450 from rabbit nasal microsomes. Biochemistry1988;27:8330.

33 Smith CAD, Gough AC, Leigh PN, et al. Debrisoquine hydroxylase gene

polymorphism and susceptibility to Parkinson's disease. Lancet 1992;339:1375-7.

34 Kondo I, Kanazawa I. Association of Xba I allele (Xba I 44kb) ofthe human cytochrome P-450dbl (CYP2D6) gene in Japanese patientswith idiopathic Parkinson's disease. In: Nagatsu T, Narabayashi H,Yoshida M, eds. Key topics in brain research: Parkinson's disease. Fromclinical aspects to molecular basis, New York: Springer-Verlag, 1991;111-7.

35 Green S, Buttrum S, Molloy H, et al. N-methylation of pyridines inParkinson's disease. Lancet 199 1;338: 120-1.

36 Humphry CDN, Steventon GB, Sturman SG, Waring RH, Griffiths B,Williams AC. Monoamine oxidase substrates in Parkinson's disease.Biochem Pharmacol 1990;11:2562-4.

37 Bonuccelli U, Piccini P, Del Dotto P, Pacifici GM, Corsini GU,Muratorio A. Platelet monoamine oxidase B activity in Parkinsonianpatients. J Neurol Neurosurg Psych 1990;53:854-5.

38 Chiba K, Trevor A, Castagnoli N Jr. Metabolism of the neurotoxic ter-tiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys ResCommonu 1984;120:574-8.

39 The Parkinson Study Group. Effect of deprenyl on the progression of dis-ability in early Parkinson's disease. N EngJ Med 1989;322:1364-71.

40 Widner H, Tetrud J, Rehncrona S, et al. Bilateral fetal mesencephalicgrafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MP'TP). New Eng J Med 1992;327:1556-61.

41 Steventon G, Heafield MTE, Waring RH, Williams AC. Xenobioticmetabolism in Parkinson's disease. Neurology 1989;39:883-7.

42 Steventon G, Williams AC, Waring RH, Pall HS, Adams D. Xenobioticmetabolism in motorneuron disease. Lancet 1988;i:644-7.

43 Heafield MTE, Feam S, Steventon GB, Waring RH, Williams AC,Sturman SG. Plasma cysteine and sulphate levels in patients with motorneurone Parkinson's and Alzheimer's disease. Neurosci Lett 1990;110:216-20.

44 Heafield MTE, Waring RH, Sturman SG, Steventon GB, Williams AC,Thompson H. N-Acetylation status in neurodegenerative disease. MedSci Res 1990;18:963-4.

45 Waring RH, Steventon G, Heafield MTE, Sturman SG, Williams AC,Smith M. S-methylation in Parkinson's disease and motor neuronedisease. Lancet 1989;ii:356-7.

Neurological stamp

Philippe Pinel (1745-1826)

When Philippe Pinel was physician to the Hospice deBicetre, the Paris asylum for men, he authorised removalof the chains that restrained the patients. The uncon-trolled behaviour of the men, that others had predicted,did not occur.

Pinel was convinced that insane people needed treat-ment and were not possessed by a devil. His theory thatinsanity was a mental illness was not received favourablyby the medical profession. His influence, however, led toa far more enlightened approach to the treatment ofthose that were mentally ill.

In 1801 Pinel published a full account of his new tech-niques in his Traite Medeco-Philosophique sur l'alienationmentate ou la manie (Medico-Philosophical Treatise on

Mental Alienation of Mania). Three years earlier he hadpublished Nosographie Philosophique which was an

attempt to classify diseases in the way Linnaeus hadearlier classified animals.

This stamp was issued in 1958 as part of a set honour-ing French doctors (Stanley Gibbons 1367, Scott 865).

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