Cholinesterases acetylcholinesterase inhibition

ACETYLCHOLINESTERASE INHIBITING PESTICIDES Cholinesterase activity in red Discretionary 70% of individuals Ns... 

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). 

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. 

To avoid the undesirable effects of excess cholinergic stimulation, ACh is rapidly hydrolyzed after its release at the synapse by an enzyme named acetylcholinesterase AChE. A similar enzyme, butylcholinesterase BuChE also occurs. If the cholinesterase is inhibited, the ACh is not hydrolyzed so rapidly, and levels of ACh rise. 

Schaumann OO found that pretreatment of mice with 2-PAM 1 reduced inhibition of acetylcholinesterase in brain by paraoxon much more effectively than those by DFP and 217-A0. The finding of some protection against all three OP compounds could depend on direct reaction between the last two inhibitors and the oxime, with a reduction in inhibition of the enzyme. A similar consideration applies to the report by Bisa et al. that IV protected serum and brain cholinesterase from inhibition by paraoxon administered later at twice the LD5O. Although the same intraperitoneal dose of IV (7 mg) was found to protect the cholinesterase of rat serum and brain only incompletely from inhibition by DFP at 5 times the LD50, that of serum recovered its normal activity by 20 h after the dose of DFP, whereas that of brain required 26 h for recovery. 

PAM is given to regenerate inhibited cholinesterase (acetylcholinesterase) enzyme at all affected sites (Schenker et al. 1992 Shankar 1967, 1978). The available information sufficiently satisfies the need for methods of reducing toxic effects. Therefore, further studies in this regard are not required. 

Weinstock M, et al. Acetylcholinesterase inhibition by novel carbamates a kinetic and nuclear magnetic resonance study. In Multidisciplinary Approaches to Cholinesterase Functions. Velan B (Ed.). Plenum Press, New York, 1992,... 

Cholinesterase inhibitor (inhibits both acetylcholinesterase and butyrylcholinesterase) cognitive enhancer... 

FIGURE 69.2. Reaction scheme of acetylcholinesterase inhibition, reactivation, and protection activities. OPH, 2-PAM, and paraoxon are used in the example. Reaction (I) - cholinesterase AChE reaction with ASCh Reaction (II) - inhibition of AChE inhibition by paraoxon Reaction (III) - aging of AChE associated with OP exposure Reaction (TV) -reactivation of AChE by 2-PAM Reaction (V) - hydrolysis of paraoxon by OPH Reaction (VI) - reaction of 2-PAM oxime with ASCh and Reaction (VII) - DTNB reaction with SCh. The indicates a photometrically detectable metabolite. 

Cholinesterase inhibition can sometimes persist for weeks thus, repeated exposures to small amounts of this material may result in accumulation of acetylcholinesterase inhibition with possible sudden-onset acute toxicity. Chlorpyrifos may be capable of causing organophosphate-induced delayed neurotoxicity in humans a massive overdose resulted in signs characteristic of delayed neurotoxicity. Animal studies generally indicate, however, that doses several times higher than the LD50 would be required to initiate delayed neurotoxicity. 

The toxicity of dichlorvos is due to inhibition of acetylcholinesterase and the signs of toxicity are generally similar to those caused by other organo-phosphorus insecticides. Dichlorvos is a direct inhibitor of cholinesterases thus, toxicity rapidly follows exposure and recovery is also rapid. With inhalation exposures, airway acetylcholinesterase inhibition is possible in the absence of significant blood enzyme inhibition. The fly head acetylcholinesterase appears more sensitive to inhibition by dichlorvos relative to mammalian brain acetylcholinesterase. At high doses, dichlorvos may cause hyperglycemia and abnormal glucose tolerance. 

With repeated exposures, acetylcholinesterase inhibition can persist without indications of toxicity. In most cases, cholinesterase inhibition is without overt effects. Methyl parathion cannot cause delayed neurotoxicity. 

Cholinergic medication (cholinesterase inhibitors, anticholinesterase) has either a direct- or indirect-acting effect on receptor sites. Direct and indirect effects inhibit the action of the enzyme cholinesterase (acetylcholinesterase). By inhibiting cholinesterase, more acetylcholine is available to stimulate the receptor and remains in contact with the receptor longer. 

In a similar study using PET technology to assess the impact of cholinesterase inhibition in the cortical brain, Bohnen and colleagues enrolled 14 subjects with Alzheimer s disease who were administered donepezil for 12 weeks. Their data showed a 19 % donepezil induced acetylcholinesterase inhibition with most of the inhibition occurring at the anterior cingulate cortex [61]. The degree of acetylcholinesterase inhibition was limited in the cortex when compared with the 70-90% acetylcholinesterase inhibition normally found in peripheral red blood cells [62]. This implies that the cholinesterase in-... 

---