Inhibition of insulin production by cyproheptadine in RINm5F rat insulinoma cells.
The clonal insulin producing cell line RINm5F was evaluated as a model for the action of cyproheptadine (CPH)-like diabetogenic compounds in the rat pancreas. Treatment with 10 microM CPH and selected structural analogs under culture conditions produced a progressive loss of cellular insulin which reached 30% of control within 24 hours. Comparison of the activities of the analogs 4-diphenylmethylpiperidine (4-DPMP) and 2-diphenylmethylpiperidine (2-DPMP) to produce cellular insulin depletion showed that 4-DPMP was as active as CPH but 2-DPMP had no activity at the highest concentration employed (10 microM). The CPH metabolite desmethyl CPH-epoxide was five times more active than the parent compound in producing loss of insulin in RINm5F cells. These results are consistent with previously published results of CPH actions in vivo. An inhibition of insulin biosynthesis with no loss of preproinsulin mRNA occurred in RINm5F cells treated with CPH or DMCPH-epoxide. This suggests that an effect on transcription may not be the primary action by which CPH and its analogs inhibit insulin synthesis in vivo.
Miller
C P
CP
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Reape
T J
TJ
Fischer
L J
LJ
D000818:Animals; D015152:Blotting, Northern; D003533:Cyproheptadine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D007202:Indicators and Reagents; D007328:Insulin / Q000096:biosynthesis*; D007340:Insulinoma / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D014407:Tumor Cells, Cultured
D007202:Indicators and Reagents; D007328:Insulin; D010880:Piperidines; D012333:RNA, Messenger; C056520:4-diphenylmethylpiperidine; D003533:Cyproheptadine; C084901:2-diphenylmethylpiperidine; C060926:desmethylcyproheptadine 10,11-epoxide; D004247:DNA