Skip Navigation



ToxSci Advance Access published online on March 31, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh113
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
79/2/258    most recent
kfh113v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hawkins, B. S.
Right arrow Articles by Fischer, L. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hawkins, B. S.
Right arrow Articles by Fischer, L. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Received November 24, 2003; accepted February 6, 2004
© 2004 Toxicological Sciences © Society of Toxicology 2004; all rights reserved.

Endocrine Toxicology

Inhibition of Insulin Synthesis by Cyproheptadine: Effects on Translation

Belinda S. Hawkins 1 and Lawrence J. Fischer 1*

1 Michigan State University, Institute for Environmental Toxicology and Department of Pharmacology and Toxicology, East Lansing, Michigan

* To whom correspondence should be addressed. E-mail: lfischer{at}msu.edu.


  Abstract

The antihistaminic, antiserotonergic drug cyproheptadine (CPH) is known to inhibit insulin synthesis in vivo and in vitro. This inhibition of insulin synthesis occurs without a commensurate decrease in preproinsulin mRNA (PPImRNA) levels, suggesting a post-transcriptional mechanism of action. The goal of the present study was to investigate the direct effects of CPH on translation of PPImRNA in RINm5F cells. Results produced using a subcellular fractionation technique followed by real-time RT-PCR indicated that a 2 hour 10µM CPH treatment resulted in a decrease in the percentage of cellular PPImRNA associated with endoplasmic reticulum (ER) bound polysomes and increases in the percentages of translationally-uninitiated and monoribosome-associated PPImRNA. These alterations in PPImRNA distribution were found to be concentration-dependent, chemical structure-specific, and reversible with a time course consistent with a previously reported CPH-induced inhibition of insulin synthesis previously reported. Further investigations to examine a possible the effect of CPH on translation initiation were then undertaken by examining the phosphorylation state of the translation initiation factors eIF2{alpha}, eIF4E, and 4E-BP1 after CPH treatment. CPH (10 µM) treatment resulted in increased phosphorylation of eIF2{alpha}, and decreased phosphorylation of both eIF4E and 4E-BP1. These changes are all consistent with decreased initiation of translation. Taken together, these results suggest that the inhibition of insulin synthesis known to be elicited by CPH treatment of RINm5F cells and intact animals involves alterations of initiation factor phosphorylation leading to a decrease in insulin synthesis and of stored insulin in insulin-producing cells.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Toxicol SciHome page
M. A. Otieno, N. Bavuso, J. Milano, L. Foster-Brown, K.-H. Bui, Y. Li, T. Hudzik, D. Wescott, C. Louden, M. Dyroff, et al.
Mechanistic Investigation of N,N-Diethyl-4-(phenyl-piperidin-4-ylidenemethyl)-benzamide-Induced Insulin Depletion in the Rat and RINm5F Cells
Toxicol. Sci., September 1, 2008; 105(1): 221 - 229.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.