Carbamate and carbamate-based pesticides exhibit their toxic action via inhibition of acetylcholinesterase, an enzyme found in nicotinic and muscarinic receptors in nerve, muscle, gray matter of the brain, and red blood cells. Inhibition of this enzyme leads to central, parasympathetic, and sympathetic neurotoxicity (45).

Most organophosphates (especially the nerve gases) induce irreversible phosphorylation of the serine hydroxyl moiety at the binding site of the enzyme, thus reducing the esterase activity. This block may be reversed by the administration of the commonly used specific antidote pralidoxime (2-PAM), but with passage of time the natural cellular proteinases are activated and the majority of poisoned enzyme is taken inside the cell (thus rendering it inaccessible to the action of 2-PAM) and proteolytically destroyed within 24 hours. Although the rate of synthesis of acetylcholinesterase in the neuron has not been measured with satisfactory precision, the much more easily measured enzyme levels in the erythrocyte increase very slowly, by less than 1% a day (46).

Acetylcholinesterase inhibition induced by carbamate-based pesticides is reversible, and the agents themselves have poor ability to penetrate the blood-brain barrier, which limits their clinical significance as neurotoxic agents (45,46).

In addition to the well-established rapid toxicity related to the cholinergic crisis, some of the organophosphates exhibit delayed neurotoxicity, which is due to their ability to induce axonal pathology and resulting polyneuropathy. This area of research is controversial, as is the association of preventive use of antidotes during the first Gulf War. In several well-established cases of organophosphorous ester-induced delayed neuropathy, patients have developed the condition as a result of both acute and cumulative exposure, with a significant time delay factor (more than a week) after single acute exposures and an even less certain and more expanded latent period in chronic exposure. Typically, the spinal cord tracts and distal axons of the lower extremities are involved more than the upper extremities. Primary axonopathy is accompanied by secondary demyelination in which both sensory and motor fibers are involved. The delayed toxicity is not due to acetylcholinesterase poisoning but rather a result of phosphorylation of a receptor protein. In complicated cases of neuropathy following pesticide exposure, a sural nerve biopsy may be performed and blood samples may be analyzed for the levels of the target protein (45,46).

A unique case addressed neuropathic changes observed in a middle-aged man who had one episode of exposure to sarin during the 1995 terrorist attack in a Tokyo subway. Peripheral nerve biopsy found severe sensory and motor fiber loss and a postmortem examination revealed nearly total loss of myelinated fibers in the white matter of the spinal cord with apparent sparing of the posterior columns. Brain changes were also found to be consistent with hypoxic-ischemic encephalopathy (47).

Genetic predisposition may play a role in the development of chronic exposure-induced delayed neurotoxicity. At least two research groups found the correlation between the development of Parkinson's disease as a result of exposure to organophosphate pesticides and genetic polymorphisms of glu-tathione transferase, an antioxidant enzyme. As dopamine is the only known major neurotransmitter that produces an active (and toxic) free radical when metabolized by monoaminooxidase, patients with decreased cellular proxi-dant scavenging ability may be more susceptible to development of Parkinson's disease and dementia with Lewy bodies (44,48,49).

Elbaz and colleagues (50) performed a case-control study of Parkinson's disease in a population characterized by a high prevalence of pesticide exposure. The authors also studied the joint effect of pesticide exposure and the activity of a cytochrome CYP2D6, a protein commonly implicated in the association between pesticide neurotoxicity and the development of Parkinson's disease. The authors found that pesticides have a modest effect of increasing the incidence of Parkinson's disease in subjects who are not CYP2D6 poor metabolizers and that the effect of pesticides is increased approximately twofold in poor metabolizers. This study also found that individuals who are CYP2D6 poor metabolizers are not at increased Parkinson's disease risk in the absence of pesticide exposure (51).

Another commonly implicated protein that may be a part of the pesticide exposure link to neurodegenerative disease is alpha-synuclein, a small, highly charged protein expressed predominantly in neurons. It is the major building block of pathological inclusions that characterize many neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies (DLB), and neurodegeneration with brain iron accumulation type 1 (NBIA-1), which collectively are termed synucleinopathies. Several ongoing studies have established preliminary links between exposure to pesticides with abnormal levels of expression of synuclein and related proteins (52).

Alpha-synuclein is a presynaptic protein characterized by the lack of rigid well-defined structure. This protein may either stay unfolded or adopt an amyloidogenic folded conformation. It also might form several morphologically different types of aggregates, including oligomers, amorphous aggregates, and/or amyloid-like fibrils. This plasticity may explain why a single protein is believed to be involved in such a varied spectrum of neurodegener-ative diseases. Preliminary evidence suggests that the ultimate structural fate of this and other amyloidogenic proteins depends on the levels of free radicals in tissue. This finding may explain the presence of the cytochrome system inhibition in the clinical history of some of the patients, as the malfunctioning cytochrome system is a known source of free radicals (53,54).

While measurement of synuclein in the brain tissue remains technically difficult, the issue of inhibition and induction of CYP2D6 is much more real and practical for all physicians. Table 23.5 summarizes current knowledge of the chemicals that induce and inhibit this cytochrome. Physicians may be well served by noting the connection between CYP2D6 status and prescribing

Table 23.5. Chemical compounds and cytochrome 2D6.

CYP2D6 substrates

CY2D6 inducers

CYP2D6 inhibitors

Most tricyclic antidepressants: amitriptyline, Carbamazepine nortriptyline, clomipramine, desipramine, imipramine, doxepin Many antipsychotics: clozapine, risperidone, Phenobarbital chlorpromazine, haloperidol, fluphenazine, thioridazine

Opioids and opioid-like analgesics: codeine, Phenytoin hydrocodone, oxycodone, morphine, methadone meperidine, tramadol Some antidepressants: fluoxetine, paroxetine, Rifampin venlafaxine, trazodone Many beta-1-blockers: bisoprolol, metoprolol, Ritonavir propranolol, timolol Alzheimer's disease medication: donepezil Antiarrhythmics: flecainide, mexiletine, propafenone Stimulants: methamphetamine






Fluphenazine Haloperidol








Source: Data from Michalets (55).

medications that are less likely to inhibit this enzyme or to compete with other substrates, such as pesticides (55).

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