Human small bowel as model for poisoning with organophosphorus compounds.

Abstract

In previous experiments, human and rat small bowel samples have been successfully used to study the spasmolytic effect of (potential) therapeutics in carbamate-constricted bowel specimens. Additionally, transferability from rat to human data was shown in the previous study. In the present study, the effects of atropine, scopolamine, MB327, HI-6 as well as obidoxime were examined in organophosphorus-poisoned human small bowel specimens. All substances were tested with at least seven concentrations in samples previously exposed to the nerve agent sarin. Furthermore, the cholinesterase reactivation potential of all substances was investigated. The test substances displayed a spasmolytic effect allowing the calculation of dose-response curves and EC50s. The parasympatholytic compound scopolamine had the strongest relaxing effect (EC50 = 0.05 μM) followed by atropine (EC50 = 0.07 μM). HI-6 and obidoxime were capable to reactivate the sarin-inhibited cholinesterase activity in small bowel samples. Both substances restored AChE activity in a dose-dependent way, with HI-6 being more potent (HI-6 EC50 = 3.8 μM vs obidoxime EC50 = 197.8 μM). Summarizing, our isolated human small bowel setup is a suitable tool to investigate the smooth muscle relaxing effect of (candidate) therapeutics for organophosphorus compound poisoning i.e. sarin exposure in a complex 3D tissue model.

• Authors: Katharina Marquart, Olga Prokopchuk, Dirk Wilhelm, Franz Worek, Horst Thiermann, Marc E Martignoni, Timo Wille
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 57 Pg. 76-80 (Jun 2019) ISSN: 1879-3177 [Electronic] England
• PMID: 30763608 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Cholinesterase Inhibitors
• Cholinesterase Reactivators
• Sarin
• Cholinesterases

Topics

• Adult
• Aged
• Aged, 80 and over
• Cholinesterase Inhibitors (toxicity)
• Cholinesterase Reactivators (pharmacology)
• Cholinesterases (metabolism)
• Female
• Humans
• Intestine, Small (drug effects, physiology)
• Male
• Middle Aged
• Muscle Relaxation (drug effects)
• Muscle, Smooth (drug effects, physiology)
• Organophosphate Poisoning
• Sarin (toxicity)
• Young Adult