Cholinesterase, marker

Consistent decreases in plasma cholinesterase may not have been observed in rats and dogs because they were treated with lower doses of diisopropyl methylphosphonate. In general, depression of plasma cholinesterase, also known as pseudocholinesterase or butyrylcholinesterase, is considered a marker of exposure rather than an adverse effect. Depression of cholinesterase activity in red blood cells (acetylcholinesterase) is a neurological effect thought to parallel the inhibition of brain acetylcholinesterase activity. It is considered an adverse effect. Acetylcholinesterase is found mainly in nervous tissue and erythrocytes. Diisopropyl methylphosphonate was not found to inhibit RBC... 

Although this study (Hart 1980) did not identify an effect level, the NOAEL is below the LOEL found in all studies examining the toxicity of diisopropyl methylphosphonate. The LOEL for diisopropyl methylphosphonate is 262 mg/kg/day for male mink and 330 mg/kg/day for female mink (Bucci et al. 1997), doses at which statistically significant decreases in plasma cholinesterase (butyrylcholinesterase) but not RBC cholinesterase (acetylcholinesterase) activity were observed (Bucci et al. 1997). In general, a decrease in plasma cholinesterase activity is considered to be a marker of exposure rather than a marker of adverse effect, while a decrease in RBC acetylcholinesterase activity is a neurological effect thought to parallel the inhibition of brain acetylcholinesterase activity and is thus considered an adverse effect. Diisopropyl methylphosphonate was not found to inhibit red blood cell cholinesterase at doses at which plasma cholinesterase was significantly inhibited. No effects were observed in males at 45 mg/kg/day (Bucci et al. 1997) or at 63 mg/kg/day (Bucci et al. 1994), and no effects were observed in females at 82 mg/kg/day (Bucci et al. 1994), or at 57 mg/kg/day (Bucci et al. 1997). 

It is well established that acetylcholine can be catabolized by both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) these are also known as "true" and "pseudo" cholinesterase, respectively. Such enzymes may be differentiated by their specificity for different choline esters and by their susceptibility to different antagonists. They also differ in their anatomical distribution, with AChE being associated with nervous tissue while BChE is largely found in non-nervous tissue. In the brain there does not seem to be a good correlation between the distribution of cholinergic terminals and the presence of AChE, choline acetyltransferase having been found to be a better marker of such terminals. An assessment of cholinesterase activity can be made by examining red blood cells, which contain only AChE, and plasma. 

The major action resulting from human exposure to diazinon is the inhibition of cholinesterase activity (refer to Section 2.4 for discussion). Two pools of cholinesterases are present in human blood acetylcholinesterase in erythrocytes and serum cholinesterase (sometimes referred to as pseudocholinesterase or butyrlcholinesterase) in plasma. Acetylcholinesterase, present in human erythrocytes, is identical to the enzyme present in neural tissue (the target of diazinon action) while serum cholinesterase has no known physiological function. Inhibition of both forms of cholinesterase have been associated with exposure to diazinon in humans and animals (Coye et al. 1987 Edson and Noakes 1960 Soliman et al. 1982). Inhibition of erythrocyte, serum, or whole blood cholinesterase may be used as a marker of exposure to diazinon. However, cholinesterase inhibition is a common action of anticholinesterase compounds such as organophosphates (which include diazinon) and carbamates. In addition, a wide variation in normal cholinesterase values exists in the general population, and there are no studies which report a quantitative... 

It should be noted that serum cholinesterase activity has been reported to be a more sensitive marker for diazinon exposure than erythrocyte acetylcholinesterase (Endo et al. 1988 Hayes et al. 1980). In light of this, it has been suggested that in the absence of baseline values for cholinesterase activity, sequential post-exposure cholinesterase analyses be used to confirm a diagnosis of organophosphate poisoning (Coye et al. 1987). 

Methods for Determining Biomarkers of Exposure and Effect. Section 2.6.1 reported on biomarkers used to identify or quantify exposure to diazinon. Some methods for the detection of the parent compound in biological samples were described above. The parent chemical is quickly metabolized so the determination of metabolites can also serve as biomarkers of exposure. The most specific biomarkers will be those metabolites related to 2-isopropyl-6-methyl-4-hydroxypyrimidine. A method for this compound and 2-(r-hydroxy-l -methyl)-ethyl-6-methyl-4-hydroxypyrimidine in dog urine has been described by Lawrence and Iverson (1975) with reported sensitivities in the sub-ppm range. Other metabolites most commonly detected are 0,0-diethylphosphate and 0,0-diethylphosphorothioate, although these compounds are not specific for diazinon as they also arise from other diethylphosphates and phosphorothioates (Drevenkar et al. 1993 Kudzin et al. 1991 Mount 1984 Reid and Watts 1981 Vasilic et al. 1993). Another less specific marker of exposure is erythrocyte acetyl cholinesterase, an enzyme inhibited by insecticidal organophosphorus compounds (see Chapter 2). Methods for the diazinon-specific hydroxypyrimidines should be updated and validated for human samples. Rapid, simple, and specific methods should be sought to make assays readily available to the clinician. Studies that relate the exposure concentration of diazinon to the concentrations of these specific biomarkers in blood or urine would provide a basis for the interpretation of such biomarker data. 

Statistically significant, dose-related decreases in serum cholinesterase levels (marker for exposure to diazinon) were noted in males and females beginning at doses of 0.02 and 5.6 mg/kg, respectively. Significant reductions in erythrocyte and brain acetylcholinesterase levels were noted in males and... 

Cholinesterases (ChE) are well-known targets for organophosphates (OPs), and RVX is no exception. Much less information is available about other enzymes that could be primary targets upon exposure to low doses of OP, and on biochemical markers of possible delayed effects of OP intoxication when the level of ChE activities is the same as the control. However, this problem is very important due to various reasons, among which is fulfillment of chemical weapon agents (CWAs) nonproliferation conventional programs and inherent possibility of accidental exposure of... 

Identifying biochemical markers. These are typically sublethal biological responses to chemical pollution which are not immediately apparent. For example, genotoxic carcinogens can cause measurable DNA adduct formation, while neurotoxins, such as organophosphate pesticides, can cause reductions of cholinesterase levels in invertebrates. 

Several urinary enzymes are useful in the assessment of nephrotoxicity, and these are discussed separately in Chapter 4. Although there is some application of cholinesterases in studying hepatotoxicity, these enzymes are important markers in pesticide-induced toxicities and are discussed in Chapter 11. Creatine kinase (CK) remains a useful marker for myotoxicity, but it is rapidly losing its place to troponins in the detection of cardiotoxicity (see Chapter 7). Amylase and lipase remain the enzyme markers of pancreatic toxicity. 

Monnet-Tschudi, E. Zurich, M. G., Schiller, B., Co,sta, L. G., and Honegger, P, (2000). Maturation-dependent effects of chlorpyrifos and paraihion and their oxygeti analogs o iieetyl-cholinesterase and neuronal and glial markers in aggregating brain cell cultures. Toxicol. Appl. Pharmacol. 165, 175-183. 

Although erythrocyte cholinesterase is invariably more specific than BuChE activity as a marker of OP insecticide exposure, some OP insecticides (c,g,. chlorpyrifos, deme-lon, and malathion) depress plasma BuChE activity to a greater degree. 

Grauer, E., Ben Nathan, D., Lustig, S., Kobiler, D., Kapon, J., and Danenberg, H.D. (2001). Viral neuroinvasion as a marker for BBB integrity following exposure to cholinesterase inhibitors. Life Set, 68, 985-990. 

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