Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets
- Univ. of Iowa, Iowa City (USA)
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.
- OSTI ID:
- 5364780
- Journal Information:
- Cell Biology and Toxicology; (USA), Vol. 5:2; ISSN 0742-2091
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANTIHISTAMINICS
BIOCHEMICAL REACTION KINETICS
INSULIN
BIOSYNTHESIS
FETUSES
IN VITRO
INHIBITION
LEUCINE
LIQUID COLUMN CHROMATOGRAPHY
METABOLITES
PANCREAS
RATS
SECRETION
TRACER TECHNIQUES
TRITIUM COMPOUNDS
AMINO ACIDS
ANIMALS
BODY
CARBOXYLIC ACIDS
CHROMATOGRAPHY
DIGESTIVE SYSTEM
DRUGS
ENDOCRINE GLANDS
GLANDS
HORMONES
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PEPTIDE HORMONES
REACTION KINETICS
RODENTS
SEPARATION PROCESSES
SYNTHESIS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques