Interspecies differences in enzymes reacting with organophosphates and their inhibition by paraoxon in vitro

Abstract

<jats:p> 1 Inhibition of cholinesterases (ChE) and carboxyles terases (CaE) by paraoxon (Px) was studied in vitro in the serum, liver, lung and muscle of mouse, guinea pig, rabbit and man (serum only). Moreover, the role ofPx hydrolyzing enzyme (Pxase) in the detoxification of Px was studied by inhibiting its activity with EDTA. </jats:p><jats:p> 2 The ChE and CaE activities as well as their sensitivity to Px varied in different tissues and species. The ChEs were more sensitive than CaEs to Px except in the liver. The CaE activity in human and rabbit sera was low and resistant to Px, indicating that it may have a minor importance for the binding of Px. </jats:p><jats:p> 3 The Px-inhibited ChEs were spontaneously reactivated in the mouse and rabbit sera during 24 h. In mouse, also the CaE activity was recovered. The presence of EDTA in the incubation medium prevented this reactivation indicating that Pxase takes part in the reactivation process. </jats:p><jats:p> 4 In rabbit, the serum Pxase activity was very high suggesting a good Px detoxifying capacity of the rabbit serum. </jats:p><jats:p> 5 The results show that amounts and sensitivities of esterases to OPs in rodents may markedly differ from that in man. Possible species-related differences in the affinity of ChEs and CaEs for OPs and the OP hydrolyzing activity should be taken into the con sideration, when animal data are extrapolated to man. </jats:p>

Stability of cytotoxic luteinizing hormone-releasing hormone conjugate (AN-152) containing doxorubicin 14- O -hemiglutarate in mouse and human serum in vitro: Implications for the design of preclinical studies

“…In conclusion, the findings reported in this paper demonstrate that the very high CE activity in serum of nude mice, which is about 10 times higher than in human beings (19), can be inhibited by DFP, which results in a significantly longer t 1/2 and a better targeting for the cytotoxic peptide conjugates. The inhibition of CE in nude mice by DFP is very reproducible.…”

Molecular Basis of Valine-Citrulline-PABC Linker Instability in Site-Specific ADCs and Its Mitigation by Linker Design

“…It has been unclear whether human plasma might contain any carboxylesterase homologs. Earlier findings attributed some p-nitrophenyl acetate reactivity in human plasma to the presence of carboxylesterase (33,41); however, more recent studies report no carboxylesterase found in human plasma (25). It is possible that carboxylesterase might be present at a very low concentration range in the primates, similar to acetylcholinesterase levels, but be induced or secreted into the plasma under certain conditions.…”

“…Degradation of ester, thioester, and amide linkages by the mouse and rat serum carboxylesterases has been reported for a wide range of compounds, including various organophosphates, nerve agents, xenobiotics, prodrugs, and certain ADCs (33)(34)(35)(36)(37)(38). The stability of VC-PABC-based cleavable conjugates in the plasma varies greatly among different species.…”

Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters

“…Physostigmine is known to interfere with cholinesterases [28]. EDTA is known to inhibit A-esterases [34] which are capable of hydrolysing a number of aromatic carboxyl acid esters. The requirement of calcium for the activity of A-esterases was stated by Erd .…”