Cholinesterase estimations revisited: the clinical relevance.

In 1986, Whittaker wrote ‘Churchill-Davidson’s editorial entitled “The succinylcholine story” in 1963, highlighted probably for the first time in the UK, the role of serum protein polymorphism in drug sensitivity’ [1]. Following a series of detailed family studies, in 1959 Kalow [2] concluded that individuals who had prolonged apnoea following succinylcholine administration were homozygous for an atypical form of cholinesterase, the product of a gene other than that found in unaffected people [3]. This led to the introduction of the term ‘pharmacogenetics’, and cholinesterase estimations became an important biochemical investigation in anaesthesia. Subsequently, the global burden of pesticide-related disease – particularly due to the potent inhibitors of cholinesterase activity, the organophosphates – increased the importance of quantifying the activity of this enzyme in clinical practice. Most of the illhealth associated with exposure to organophosphates has been attributed to inhibition of the enzyme acetylcholinesterase in a range of nerve, neuromuscular (skeletal, smooth, cardiac) and glandular tissues where the enzyme plays a key role in cell-to-cell communication. The existence of an esterase capable of hydrolyzing acetylcholine was suggested by Dale [4] and established by Loewi and Navratil [5]. The term ‘cholinesterase’ was proposed by Stedman and colleagues [6] for this enzyme. Subsequently, Alles and Hawes [7] demonstrated that cholinesterase in human erythrocytes differed in a preferred substrate from that in human plasma. The erythrocyte enzyme – and the enzyme in conductive tissues (in all excitable tissues: cholinergic or adrenergic, motor or sensory, peripheral or central nerve fibres, and all types of muscle fibres) – was called acetylcholinesterase, as acetylcholine is preferentially hydrolyzed. The enzyme in plasma was termed ‘butyrylcholinesterase’, as it preferentially hydrolyzed butyrylcholine and was formerly more popularly known as pseudocholinesterase. The roles of butyrylcholinesterase and that of acetylcholinesterase in erythrocytes and plasma are not known with any certainty to date, and individuals who do not possess butyrylcholinesterase lead normal lives until they are exposed to succinylcholine. Butyrylcholinesterase is involved in the hydrolysis of many therapeutic agents and, together with acetylcholinesterase in the blood, it acts as a site for phosphorylation by organophosphates, thus serving as scavengers [8]. Scavenging reduces the amount of organophosphate available for toxic effects at vulnerable targets. For both acetylcholinesterase and butyrylcholinesterase, several functions have been proposed that are not directly related to synaptic transmission, e.g. the regulation of protein–protein interactions during neurite outgrowth and synapse formation, the modulation of cell movements, and cell proliferation [9]. A variety of methods are now available for cholinesterase assays based predominantly on the measurement of the rate of hydrolysis of an ester catalysed by cholinesterase. However, as the ‘normal range’ is characteristic for each substrate and the rate of hydrolysis is temperatureand pH-dependent, confusion has arisen in the interpretation of estimations when the exacting practice of recording the substrate, pH and temperature have been omitted [1]. There are several reasons for the confusion associated with cholinesterase estimations in relation to exposure to anticholinesterases (e.g. organophosphates and carbamates). There are many causes of decreased activity of cholinesterases that are not related to exposure to anticholinesterases: genetic, physiological (age, gender, pregnancy, etc.), iatrogenic (therapeutic agents), disease states, exposure to smoke fumes and, in some instances, of uncertain origin [10–12]. There are suggestions that dietary factors can influence cholinesterase concentrations. Low concentrations of cholinesterases have been observed in malnutrition [13]. Further, with the increasing popularity of traditional medicines containing plants or plant extracts capable of lowering cholinesterase activity (e.g. solanine and chaconine in potatoes, Correspondence to: Lakshman Karalliedde, Medical Toxicology Unit and National Poisons Centre (London), Guy’s and St Thomas’ NHS Trust, Avonley Road, London, SE14 5ER, UK. E-mail: [email protected]; Tel: 1 44 (0)207 771 5315/5202; Fax: 1 44 (0)207 771 5306