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ToxSci Advance Access published online on June 6, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn108
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mechanistic Investigation of N,N-diethyl-4-(phenyl-piperidin-4-ylidenemethyl)-benzamide -induced Insulin depletion in the rat and RINm5F Cells.

Monicah A. Otieno*,{dagger}, Nicole Bavuso{ddagger}, Joseph Milano, Linda-Foster Brown, Khanh-Hui Bui§, Yan Li§, Thomas Hudzik, Debra Wescott{dagger}, Calvert Louden, Martin Dyroff and François Pognan||

Safety Assessment US, AstraZeneca Pharmaceuticals, Wilmington, Delaware, 19850 § DMPK, AstraZeneca Pharmaceuticals, Wilmington, Delaware, 19850 Neuroscience, AstraZeneca Pharmaceuticals, Wilmington, Delaware, 19850

* Corresponding Author Monicah. A. Otieno, Bristol Myers-Squibb, Discovery Toxicology Lawrenceville, Mail Stop F14-01, Route 206 & Provinceline Road, Princeton, NJ 08543. Tel: 609 252-5564; Fax: 609 252-7156; email: monicah.otieno{at}bms.com.

Received March 11, 2008; revision received May 21, 2008; accepted May 23, 2008


  Abstract

These studies describe the effect of N,N-diethyl-4-(phenyl-piperidin-4-ylidenemethyl)-benzamide (AR-M100390) , a delta opioid agonist, on the pancreas and its mechanisms for pancreatic toxicity. Rats were treated with 5, 100, and 600 µmol/kg of AR-M100390 for 3 and/or 7 days; another group of rats treated with 600 µmol/kg of compound were allowed to recover for 14 days. AR-M100390 (600 µmol/kg) caused vacuolation in the β-cell of the rat pancreas that was associated with depletion of insulin and hyperglycemia after 7 days of dosing. The loss of insulin by AR-M100390 was due to specific inhibition of rat insulin2 mRNA transcription in vivo. Insulin depletion and hyperglycemia were reversible. The effects of AR-M100390 in rats was reproduced in the rat pancreatic β-cell line RINm5F, where it inhibited intracellular insulin content and secretion without affecting cell survival. Loss of insulin in vitro was also a result of specific inhibition of insulin2 mRNA transcription and was reversible. Pre-treatment of cells with the {delta}-opioid antagonist naltrindole or pertussis toxin did not reverse loss of insulin in AR-M100390-treated cells suggesting that the effects were not mediated by the {delta}-opioid receptor. AR-M100390 inhibited KCl-mediated calcium mobilization in RINm5F cells, suggesting that L-type calcium channels found in these cells and in pancreatic β-cells may partially play a role in the inhibition of insulin secretion by this compound. In summary, the in vitro and in vivo studies suggest that inhibition of insulin by AR-M100390 is due to a combination of inhibition of insulin synthesis and/or release.

Key Words: AR-M100390; cyclizine; pancreas; insulin; rat; RINm5F.

{dagger} Present address: Monicah. A. Otieno, Bristol Myers-Squibb, Discovery Toxicology Lawrenceville, Mail Stop F14-01, Route 206 & Provinceline Road, Princeton, NJ 08543. Tel: 609 252-5564; Fax: 609 252-7156; email: monicah.otieno{at}bms.com.

{ddagger} Present address: UMDNJ - Robert Wood Johnson Medical School, Piscataway, NJ 08854.

|| Present address: Norvatis Pharma AG, Safety Profiling and Assessment, Auhafenstrasse, Switzerland.


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