Human plasma butyrylcholinesterase

VII. Effect of Human Plasma Butyrylcholinesterase as Scavenger on the Toxicokinetics... 

VII. EFFECT OF HUMAN PLASMA BUTYRYLCHOLINESTERASE AS SCAVENGER ON THE TOXICOKINETICS OF NERVE AGENTS... 

Garcia, G.E. et al. Glycan structure comparison of native human plasma butyrylcholinesterase (Hu-BChE) and transgenic goat produced Hu-BChE, FASEB J., 19, A867, 2005. 

Garcia, G.E., Moorad-Doctor, D., Doctor, B.P., Saxena, A., Lockridge, O., Lenz, D.E., Cerasoli, D., and Huang, Y. 2005, Glycan structure comparison of native human plasma butyrylcholinesterase (Hu-BChE) and transgenic goat produced Hu-BChE, FASEB J., vol. 19, p. A867. 

Li B, Sedlacek M, Manoharan I, Boopathy R, Duysen EG, Masson P, Lockridge O (2005) Butyrylcholinesterase, paraoxonase, and albumin esterase, but no carboxylesterase, are present in human plasma. Biochem Pharmacol 70 1673-1684... 

Kolarich, D., Weber, A., Pabst, M., Stadlmann, J., Teschner, W., Ehrlich, H., Schwarz, H.P., Altmann, F. (2008). Glyco-proteomic characterization of butyrylcholinesterase from human plasma. Proteomics 8 254-63. 

Lockridge, O., Schopfer, L.M., Winger G., Woods, J.H. (2005). Large scale purification of butyrylcholinesterase from human plasma suitable for injection into monkeys a potential new therapeutic for protection against cocaine and nerve agent toxicity. J. Med. GBR Def. 5 1-20. 

Fidder et al. introduced an electrospray-ionization tandem mass spectrometry method for diagnosing OP exposure by measuring the mass of the OP-labeled active site peptide of human butyrylcholinesterase (Fidder et al, 2002). His starting material was 0.5 ml of human plasma from a victim of the Tokyo subway attack. The mass of the active site peptide was higher by 120 atomic mass units, compared to the mass of the unlabeled active site peptide. This added mass was exactly the added mass expected from sarin. The peptide s MS-MS fragmentation spectrum yielded the sequence of the peptide, and verified that the OP label was on serine 198, the active site serine. Examples of the MS-MS spectra from tryptic peptides of pure, OP-labeled human butyrylcholinesterase are shown in Figure 56.1. 

Both intensity and length of exposure play important roles in determining the extent of inhibition of NTE in lymphocytes 50% of preexposed values of NTE activity were obtained when measured 3 or 4 weeks after the beginning of DEF exposure. However, there is no direct evidence of a correlation between a high level of lymphocyte NTE inhibition and development of neuropathy in humans. Blood acetylcholinesterase and plasma butyrylcholinesterase levels remained unchanged during the study period. There is no available weight-of-the-evidence summary assessment for DEF as a developmental or reproductive toxin. 

Several authors have measured the relative molecular mass of purified butyrylcholinesterase from horse or human plasma. The earlier findings (Table 12) differ considerably from the more recent results. Inspection of... 

The effects of inorganic salts on plasma cholinesterase (E16) are largely contradictory. Fruentova (F9) reported that divalent cations are more effective inhibitors of horse serum cholinesterase than are monovalent ions, whereas divalent ions are frequently reported to have a marked activating effect (H38, T8, VI). Lithium and sodium nitrates have been shown by in vitro studies of the reaction of human plasma cholinesterase with benzoylcholine to have identical inhibition profiles (W21), while sodium and potassium chlorides had very similar inhibitory actions on the hydrolysis of acetylcholine by human plasma (H47). Silver nitrate, copper sulfate, and mercuric chloride are powerful inhibitors of F. polycolor butyrylcholinesterase (N2). Cohen and Oosterbaum (C12) concluded that activation by cations occurring at the usual substrate concentration is highly dependent on the experimental conditions. This supposition is very relevant to the somewhat random choice of buffers and substrates in the work reported above. 

Li, B., Ricordel, I., Schopfer, L.M., et al., 2010a. Dichlorvos, chlorpyrifos oxon and Aldicarb adducts of butyrylcholinesterase, detected by mass spectrometry in human plasma following deliberate overdose. J. Appl. Toxicol. 30 (6),... 

Schopfer, L.M., Masson, P, Lamourette, P, et al., 2014. Detection of cresyl phosphate-modified butyrylcholinesterase in human plasma for chemical exposure associated with aerotoxic syndrome. Anal. Biochem. 461, 17-26. 

Inhibition of the two principal human cholinesterases, acetylcholinesterase and pseudocholinesterase, may not always result in visible neurological effects (Sundlof et al. 1984). Acetylcholinesterase, also referred to as true cholinesterase, red blood cell cholinesterase, or erythrocyte cholinesterase is found in erythrocytes, lymphocytes, and at nerve synapses (Goldfrank et al. 1990). Inhibition of erythrocyte or lymphocyte acetylcholinesterase is theoretically a reflection of the degree of synaptic cholinesterase inhibition in nervous tissue, and therefore a more accurate indicator than pseudocholinesterase activity of inhibited nervous tissue acetylcholinesterase (Fitzgerald and Costa 1993 Sundlof et al. 1984). Pseudocholinesterase (also referred to as cholinesterase, butyrylcholinesterase, serum cholinesterase, or plasma cholinesterase) is found in the plasma, serum, pancreas, brain, and liver and is an indicator of exposure to a cholinesterase inhibitor. 

In clinical diagnosis of OP exposure, the tissue most readily available for study is blood. OP adducts of butyrylcholinesterase are better candidates for study than OP adducts on acetylcholinesterase for the following reasons. Human blood contains 5 mg of butyrylcholinesterase and 0.5 mg of acetylcholinesterase per liter. The butyrylcholinesterase is in plasma, whereas the acetylcholinesterase is bound to the membranes of red and white cells. Most OPs, with the exception of chemical warfare nerve agents, react more rapidly with butyrylcholinesterase than with acetylcholinesterase. 

Sun, W, Luo, C., Tipparaju, R, et al., 2013. Effect of polyethylene glicol conjugation on the circulatory stability of plasma-derived human butyrylcholinesterase in mice. Chem. Biol. Interact. 203, 172-176. 

Schneider, J.D., Castilho, A., Neumann, L., et al., 2013. Expression of human butyrylcholinesterase with an engineered gjycosylation profile resembling the plasma-derived orthologue. Biotechnol. J. 9,501—510. 

The activities of two enzymes have been used as biomarkers of effects for OPs, namely acetylcholinesterase (EC 3.1.1.7) and butyrylcholinesterase, sometimes known as pseudocholinesterase (EC 3.1.1.8). The structure and function of these enzymes has been reviewed. " In humans the former is present in red blood cells and the latter in plasma, but such distribution is not true of all species. In dogs, both enzymes are present in plasma with a ratio of butyrylcholinesterase to acetylcholinesterase of 7 1, while in the rat, plasma cholinesterase activity comprises more acetylcholinesterase with a butyrylcholinesterase to acetylcholinesterase activity of 1 3 in males and 2 1 in females in neither blood compartment are the functions of the enzymes fully understood.Because of the possibility of confusion, the terms plasma cholinesterase and erythrocyte cholinesterase as synonyms for butyrylcholinesterase and acetylcholinesterase are to be deprecated, especially when used of enzymes in animals where serious confusion may result. It is often necessary to look in detail at animal studies to see what activity has been measured in each matrix. In particular, it is necessary to look at the substrate(s) used in the assay together with any inhibitors used. Methods for measuring acetylcholinesterase have been reviewed and acetylcholinesterase and butyrylcholinesterase activities can be measured separately. In almost all cases it is the enzyme activity, rather than protein concentration, that is measured and many of the procedures used are variants of the Ellman method. Correct storage of blood samples is important as reactivation of inhibited enzymes ex vivo can occur. 

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