Inhibition of acetylcholinesterase activity by organic isocyanates: A possible mechanism
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JOURNAL OF APPLIED TOXICOLOGY, VOL. 11(5), 383 (1991)
Inhibition of Acetylcholinesterase Activity by Organic Isocyanates: a Possible Mechanism
H. Savolainen IUMHT, Rue du Bugnon 19, CH-1005 Lausanne, Switzerland
The inhibition of acetylcholinesterase activity in lungs by organic diisocyanates now has been demonstrated unequivocally. Earlier work in vitro has shown the transient nature of the inhibition, and it is likely that the reaction is distinct from the more general diisocyanate-protein interactions.
Bicarbonate ion strongly catalyses the hydrolysis of organic diisocyanates by water to their corresponding amines,* and this aspect has been exploited in the use of ammonium bicarbonate in the termination of reactions when synthesizing the protein-diisocynate complexes for immunological work.3
Circumstantial evidence suggests that the diisocyan- ate molecule reacts with the bicarbonate hydroxyl, forming an unstable carbamate intermediate (Fig. 1) that is hydrolysed by water to the amine and CO?, liberating the bicarbonate molecule. Thus, although not strictly speaking a catalyst, it is not consumed in the reaction sequence. The hydrolysis is 10-20 times more rapid than in the absence of 20 mM bicarbonate,
which is also its physiological concentration, so that the hydrolysis could well begin in the lung. Thus, the proximate inhibitor of the lung acetylcholinesterase could be the carbamate intermediate.
- R-NHz + COz + HCO, -
R - N = C = O
-/- Figure 1. Bicarbonate-catalysed hydrolysis of an organic diiso- acidic protons is near 6 (Ref. 21, so that a transitory complex cyanate (R-NCO) to amine and carbon dioxide. The isocyanate formation with bicarbonate could be more likely than with moiety reacts preferentially with the groups containing water. Water hydrolyses the hypothetical complex, liberating exchangeable protons. It seems that a near optimum pK, for the amine and CO,.
1. M. T. Brondeau, M. Bau, P. Simon and J. de Ceaurriz, lysed hydrolysis of hexamethylene diisocyanate to 1,6- Decrease in the rat bronchial acetylcholinesterase activity diaminohexane. Toxicol. Lett., 56, 173-178 (1991). after toluene diissocyanate inhalation. J. Appl. Toxicol., 10, 3. C. S. T. Tse and A. J. Pesce, Chemical characterisation of 423-427 (1990). isocyanate-protein conjugates. Toxicol. Appl. Pharmacol.,
2. M. Berode, B. Testa and H. Savolainen; Bicarbonate-cata- 51, 39-46 (1979).
0260-437X/91/050383-01$05 .OO 0 1991 by John Wiley & Sons, Ltd.
Received I5 January 1991 Revised 20 January 1991