Paraoxon carboxylesterase

Various esterases exist in mammalian tissues, hydrolyzing different types of esters. They have been classified as type A, B, or C on the basis of activity toward phosphate triesters. A-esterases, which include arylesterases, are not inhibited by phosphotriesters and will metabolize them by hydrolysis. Paraoxonase is a type A esterase (an organophosphatase). B-esterases are inhibited by paraoxon and have a serine group in the active site (see chap. 7). Within this group are carboxylesterases, cholinesterases, and arylamidases. C-esterases are also not inhibited by paraoxon, and the preferred substrates are acetyl esters, hence these are acetylesterases. Carboxythioesters are also hydrolyzed by esterases. Other enzymes such as trypsin and chymotrypsin may also hydrolyze certain carboxyl esters. 

Esterase activity is important in both the detoxication of organophosphates and the toxicity caused by them. Thus brain acetylcholinesterase is inhibited by organophosphates such as paraoxon and malaoxon, their oxidized metabolites (see above). This leads to toxic effects. Malathion, a widely used insecticide, is metabolized mostly by carboxylesterase in mammals, and this is a route of detoxication. However, an isomer, isomalathion, formed from malathion when solutions are inappropriately stored, is a potent inhibitor of the carboxylesterase. The consequence is that such contaminated malathion becomes highly toxic to humans because detoxication is inhibited and oxidation becomes important. This led to the poisoning of 2800 workers in Pakistan and the death of 5 (see chap. 5 for metabolism and chap. 7 for more details). 

Tissue esterases have been divided into two classes the A-type esterases, which are insensitive, and the B-type esterases, which are sensitive to inhibition by organo-phosphorus esters. The A esterases include the arylesterases, whereas the B esterases include cholinesterases of plasma, acetylcholinesterases of erythrocytes and nervous tissue, carboxylesterases, lipases, and so on. The nonspecific arylesterases that hydrolyze short-chain aromatic esters are activated by Ca2+ ions and are responsible for the hydrolysis of certain organophosphate triesters such as paraoxon (Figure 10.10B). 

Dettham, W-D., Yang, Z.P., Milatovic, D. (1999). Different role of carboxylesterases in toxicity and tolerance to paraoxon and DFP. Chem. Biol. Interact. 119-20 445-54. 

Paraoxon, the active metabolite of parathion, is a potent inhibitor of acetylcholinesterase, butyrylcholi-nesterase, and carboxylesterase, with IC50 values in the low- to mid-nanomolar range. Neither parathion nor paraoxon has been shown to be mutagenic when tested in vitro. 

Figure 9.2 Devonshire and Sawicki (1979) at Rothamstead Experimental Station, Hertfordshire, U.K., found seven variants of the aphid Myzus persicae with different resistances to parathion. Excess production of a carboxylesterase as a result of one or several gene duplications was found to be the resistance mechanism. High levels of carboxylesterases take paraoxon away from acetylcholinesterase so that aphids become resistant.

The reaction between paraoxon and carboxylesterase, rendering paraoxon unavailable for acetylcholinesterase inhibition... 

Bovine chromaffin cells in primary culture possess carboxylcstcrase activities, 73% of w-hich is NTE the NTE component is resistant to inhibition by paraoxon and sensitive to mipafox and is localized to the particulate fraction of cell culture homogenates. Results suggest that bovine chromaffin cells may be a useful model for NTE studies because they possess a higher ratio of NTE/carboxylesterase than adrenal medulla tissue homogenates, brain tissue, or nerv e. 

---