Cyproheptadine-induced alterations in rat insulin synthesis

Hintze, K. L.; Grow, Ann Baker; Fischer, Lawrence J.

doi:10.1016/0006-2952(77)90011-9

Cited by 21 publications

(9 citation statements)

References 19 publications

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“…The inhibitory effects of CPH and its metabolites on proinsulin and insulin biosynthesis were determined by measuring the incorportion of 3H_leucine into the hormones in a procedure similar to that used previously (Hintze et al, 1977). Pancreatic islets isolated from 50-day-old rats were preincubated with the test compound for 10 minutes in 1.0 ml of the incubation medium at 37°C prior to addition of the labeled amino acid.…”

Section: Effects Of Cph and Its Metabolites On (Pro)insulin Synthesismentioning

confidence: 99%

“…The head space was flushed with 95% 02/5% CO2, the tubes capped, and incubation continued for an additional 40 minutes. Under similar conditions, the incorporation of 3H-leucine into proinsulin is known to be linear with time for 60 minutes (Hintze et al, 1977). At the end of the incubation period, the incorporation of 3H-leucine was stopped by the addition of 1000-fold excess of non-labeled leucine (6.56 mg/ml).…”

Section: Effects Of Cph and Its Metabolites On (Pro)insulin Synthesismentioning

confidence: 99%

“…The drug cyproheptadine (CPH) 1 alters normal pancreatic fl-cell function in rats by inhibiting insulin biosynthesis (Hintze et al, 1977) and release (Richardson et al, 1975;Rickert and Fischer, 1975). This action is distinct from the antiserotonin, antihistaminic properties of the drug and the mechanisms for these cell specific effects have not been adequately elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets

1989

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The contribution of drug metabolites to cyproheptadine (CPH)-induced alterations in endocrine pancreatic beta-cells was investigated by examining the inhibitory activity of CPH and its biotransformation products, desmethylcyproheptadine (DMCPH), CPH-epoxide and DMCPH-epoxide, on hormone biosynthesis and secretion in pancreatic islets isolated from 50-day-old rats. Measurement of (pro)insulin (proinsulin and insulin) synthesis using incorporation of 3H-leucine showed that DMCPH-epoxide, DMCPH and CPH-epoxide were 22, 10 and 4 times, respectively, more potent than CPH in inhibiting hormone synthesis. The biosynthesis of (pro)insulin was also inhibited by CPH and DMCPH-epoxide in islets isolated from 21-day-old rat fetuses. The inhibitory action of CPH and its metabolites was apparently specific for (pro)insulin, and the synthesis of other islet proteins was not affected. Other experiments showed the metabolites of CPH were active in inhibiting glucose-stimulated insulin secretion but were less potent than the parent drug in producing this effect. CPH and its structurally related metabolites, therefore, have differential inhibitory activities on insulin synthesis and release. The observation that CPH metabolites have higher potency than CPH to inhibit (pro)insulin synthesis, when considered with published reports on the disposition of the drug in rats, indicate that CPH metabolites, particularly DMCPH-epoxide, are primarily responsible for the insulin depletion observed when the parent compound is given to fetal and adult animals.

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Section: Effects Of Cph and Its Metabolites On (Pro)insulin Synthesismentioning

confidence: 99%

Section: Effects Of Cph and Its Metabolites On (Pro)insulin Synthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets

1989

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“…The antihistaminic/antiserotonin drug cyproheptadine (CPH') selectively inhibits insulin synthesis and secretion in isolated rat pancreatic islets (1-4) and reversibly depletes pancreatic insulin and preproinsulin mRNA (PPImRNA) levels after administration to rats (1,5,6). Cyproheptadine also inhibits insulin synthesis and secretion and depletes cellular insulin content in certain insulinproducing cell lines during a 48 hour exposure period (7).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of insulin production by cyproheptadine in RINm5F rat insulinoma cells

Miller

Reape

Fischer

1993

J. Biochem. Toxicol.

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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.

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“…Pre vious studies from this laboratory using adult rats showed that the antihistaminic, antiserotonin drug, cyproheptadine (CPH), causes pancreatic beta cell (B cell) lesions after repeated oral doses [3,4], The morpho logic alterations are characterized initially by a loss of insulin secretion granules and subsequently by vacuolization of the rough endoplasmic reticulum. These changes were observed in conjunction with hyperglycemia and glucose intolerance caused by a reduc tion in serum and pancreatic insulin due to a drug-related inhibition of insulin synthesis and secretion [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Postnatal Changes in the Insulin-Depleting Action and Disposition of Cyproheptadine in Rats

Chow¹,

Fischer²

1991

Dev Pharmacol Ther

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The relationship between age-related differences in cyproheptadine (CPH)- induced alteration of endocrine pancreas function and the disposition of the drug was examined in this study. Various doses of CPH (5, 11, 22.5 or 45 mg/kg) were given orally once daily for 2 days to 10-, 15-, 25- and 50-day-old rats. Pancreatic and serum insulin measured 24 h after the second dose showed a drug-dependent decline, and the extent of this effect was dependent on the dose administered and the age of the animal. In 50-day-old rats, a significant reduction in pancreatic and serum insulin was detected only after high doses (22.5 and 45 mg/kg) of the drug. However, in 10- and 15-day-old rats, the effects were observed after the lowest dose (5 mg/kg). In separate experiments, the concentrations of CPH and its active metabolites, desmethylcyproheptadine (DMCPH), desmethylcyproheptadine-10,11-epoxide (DMCPH-epoxide) and cyproheptadine-10,11-epoxide (CPH-epoxide), were measured in the pancreas, liver and lung of neonatal and young rats at various times after the second dose of CPH (11 mg/kg). In the younger age groups (10- and 15-day-olds), there were significantly higher tissue levels of unchanged drug at all times examined. Certain of the drug metabolites known to be inhibitors of insulin synthesis had higher and/or more prolonged tissue concentrations in younger animals. For example, the metabolite CPH-epoxide was found only in tissues from younger age groups. Twenty-four hours after the second dose of CPH, no drugderived product was present in tissues of 25- and 50-day-old rats, whereas significant amounts of DMCPH-epoxide, a potent CPH metabolite inhibiting insulin synthesis, was detected in the tissues of 10- and 15-day-old rats. The data show that there are age-related differences in the susceptibility of pancreatic B cells to the actions of CPH, and that these differences are associated with age-related changes in the disposition of the drug.

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Cyproheptadine-induced alterations in rat insulin synthesis

Cited by 21 publications

References 19 publications

Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets

Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets

Inhibition of insulin production by cyproheptadine in RINm5F rat insulinoma cells

Postnatal Changes in the Insulin-Depleting Action and Disposition of Cyproheptadine in Rats

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