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Title: From cysteamine to MPTP: structure-activity studies with duodenal ulcerogens

Abstract

Cysteamine is the first chemical identified that induces acute and chronic duodenal ulcers in rodents. Structure-activity studies with cysteamine, propionitrile and their derivatives, as well as with analogues of toluene, revealed numerous alkyl and aryl duodenal ulcerogens. Among these, one of the most interesting from an etiologic and pathogenetic point of view is the dopaminergic neurotoxin MPTP, which shows structural similarities with toluene. The chemically-induced duodenal ulcers are similar and localized on the anterior and posterior wall of the duodenal bulb. Both cysteamine and MPTP affect endogenous dopamine; MPTP is especially potent in depleting central dopamine and inducing lesions in the substantia nigra. MPTP given in high doses induces Parkinson's disease-like syndrome and gastric ulcers. Cysteamine and propionitrile also cause dyskinesia in large and multiple doses. The motility disorders and duodenal ulcers are abolished by dopamine agonists. Cysteamine and MPTP have been known to increase and decrease gastric acid secretion, respectively. However, both compounds induced duodenal dysmotility, decreased bicarbonate production, and reduced its delivery from distal to proximal duodenum. These factors decrease acid neutralization in the duodenal bulb and contribute to duodenal ulceration. Thus, studies with animal models may reveal endogenous mediators and specific receptors which might be involved inmore » the pathogenesis of duodenal ulceration. Specific structure-activity studies in toxicology may lead to new insights in the pathogenesis and pharmacology of a poorly understood human disorder such as duodenal ulceration. 39 references.« less

Authors:
;
Publication Date:
Research Org.:
Brigham and Women's Hospital, Boston, MA (USA)
OSTI Identifier:
6596761
Alternate Identifier(s):
OSTI ID: 6596761
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicol. Pathol.; (United States); Journal Volume: 16:2
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; 59 BASIC BIOLOGICAL SCIENCES; CYSTAMINE; TOXICITY; DIGESTIVE SYSTEM DISEASES; PATHOGENESIS; PROPIOLONITRILE; SMALL INTESTINE; ULCERS; TOLUENE; TOXINS; BIOLOGICAL MODELS; DOPAMINE; PYRIDINES; REVIEWS; STRUCTURE-ACTIVITY RELATIONSHIPS; ALKYLATED AROMATICS; AMINES; ANTIGENS; AROMATICS; AUTONOMIC NERVOUS SYSTEM AGENTS; AZINES; BODY; CARDIOTONICS; CARDIOVASCULAR AGENTS; DIGESTIVE SYSTEM; DISEASES; DOCUMENT TYPES; DRUGS; GASTROINTESTINAL TRACT; HETEROCYCLIC COMPOUNDS; HYDROCARBONS; HYDROXY COMPOUNDS; INTESTINES; MATERIALS; NEUROREGULATORS; NITRILES; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANIC SULFUR COMPOUNDS; ORGANS; PATHOLOGICAL CHANGES; PHENOLS; POLYPHENOLS; RADIOPROTECTIVE SUBSTANCES; SYMPATHOMIMETICS; TOXIC MATERIALS 560300* -- Chemicals Metabolism & Toxicology; 550900 -- Pathology

Citation Formats

Szabo, S., and Cho, C.H. From cysteamine to MPTP: structure-activity studies with duodenal ulcerogens. United States: N. p., 1988. Web. doi:10.1177/019262338801600213.
Szabo, S., & Cho, C.H. From cysteamine to MPTP: structure-activity studies with duodenal ulcerogens. United States. doi:10.1177/019262338801600213.
Szabo, S., and Cho, C.H. Fri . "From cysteamine to MPTP: structure-activity studies with duodenal ulcerogens". United States. doi:10.1177/019262338801600213.
@article{osti_6596761,
title = {From cysteamine to MPTP: structure-activity studies with duodenal ulcerogens},
author = {Szabo, S. and Cho, C.H.},
abstractNote = {Cysteamine is the first chemical identified that induces acute and chronic duodenal ulcers in rodents. Structure-activity studies with cysteamine, propionitrile and their derivatives, as well as with analogues of toluene, revealed numerous alkyl and aryl duodenal ulcerogens. Among these, one of the most interesting from an etiologic and pathogenetic point of view is the dopaminergic neurotoxin MPTP, which shows structural similarities with toluene. The chemically-induced duodenal ulcers are similar and localized on the anterior and posterior wall of the duodenal bulb. Both cysteamine and MPTP affect endogenous dopamine; MPTP is especially potent in depleting central dopamine and inducing lesions in the substantia nigra. MPTP given in high doses induces Parkinson's disease-like syndrome and gastric ulcers. Cysteamine and propionitrile also cause dyskinesia in large and multiple doses. The motility disorders and duodenal ulcers are abolished by dopamine agonists. Cysteamine and MPTP have been known to increase and decrease gastric acid secretion, respectively. However, both compounds induced duodenal dysmotility, decreased bicarbonate production, and reduced its delivery from distal to proximal duodenum. These factors decrease acid neutralization in the duodenal bulb and contribute to duodenal ulceration. Thus, studies with animal models may reveal endogenous mediators and specific receptors which might be involved in the pathogenesis of duodenal ulceration. Specific structure-activity studies in toxicology may lead to new insights in the pathogenesis and pharmacology of a poorly understood human disorder such as duodenal ulceration. 39 references.},
doi = {10.1177/019262338801600213},
journal = {Toxicol. Pathol.; (United States)},
number = ,
volume = 16:2,
place = {United States},
year = {Fri Jan 01 00:00:00 EST 1988},
month = {Fri Jan 01 00:00:00 EST 1988}
}
  • Neutralization of acid was evaluated in rat proximal duodenal segments isolated from biliary and pancreatic secretions. Duodenal ulcerogenic doses of cysteamine produced a significant decrease in acid disposal 0.5-2 hr after treatment. Oral or subcutaneous administration of the duodenal ulcerogen was effective. The potent ulcerogen cysteamine produced a more pronounced decrease than propionitrile (a weak duodenal ulcerogen). The failure of ethanolamine, a nonulcerogenic structural analog of cysteamine to significantly alter acid disposal suggests that the effect is not due to the toxic properties of the duodenal ulcerogen. The results reinforce the concept that the duodenum is able to dispose ofmore » significant quantities of acid. The decrease in acid-handling may contribute to duodenal susceptibility to acid after treatment with ulcerogens and possibly reflects pathophysiologic changes early in duodenal ulceration.« less
  • The effect of acute or chronic administration of duodenal ulcerogens on gastric emptying (GE) of a liquid meal was investigated. In Sprague-Dawley rats (150-200g) 2 ml of /sup 51/Cr in 2% dextrose (5000 CPM) was given intragastrically and the GE half life was established as 7.6 min (controls). In acute experiments, C (30mg/100g), M (40mg/100g) or MPTP (4mg/100g) injected subcutaneously all delayed GE at 1, 2, 4, 8 and 24 hr by 15-77%. Maximal GE delay (p<0.05) by 77, 48 or 71% was found 1, 1 or 2 hr after C, M or MPTP, respectively. In chronic experiments, C (22mg/100g)more » was given x3 on the first day and once daily (25mg/100g) for 3 or 10 additional days. M (20mg/100g) once daily and MPTP (4mg/100g) x3 daily were given for 4 or 11 days. GE was measured on the 5th and 12th day. Chronically, MPTP accelerated GE by 63 and 31% at 5 and 12 days (p<0.05) and C and M did not change GE. The severity of duodenal ulcers correlated (p<0.05) with the amount of /sup 51/Cr remaining in the stomach: r=-0.68, -0.74 and -0.70 after C, M and MPTP, respectively. Acute administration of duodenal ulcerogens delay GE in rats. Chronic treatment with duodenal ulcerogens either accelerates or does not change GE. The most severe chronic ulcers exhibit the most rapid emptying. The authors data suggest that rapid GE might be a secondary rather than a primary alteration in duodenal ulceration.« less
  • Structure-activity relationships were qualitatively and quantitatively examined for 56 chemicals (e.g., derivatives of propionitrile, acrylonitrile and cysteamine) which caused duodenal ulcer and/or adrenocortical necrosis in rats. For the first time the duodenal ulcerogenic property of numerous chemicals has been studied in a rational and predictive manner. Ulcerogenic activity was most intense in the carbonitriles attached to two or three carbon backbones and diminished by shortening, lengthening, branching, unsaturating, halogenating or hydroxylating the carbon chains. Different modes of action are implied. Adrenocorticolytic potency was associated with unsaturation of the carbon chain and substitution of the nitrile by thiol or amine radicals.more » An action of these chemicals on the central nervous system has been suggested.« less
  • The glueuronide eonjugation and beta -glueuronidase activity of rai duodenal mucosa were studied after loeal x irradiation. The results show that a slight decrease was resent in the conjugation capacity of glucuronide 12 hours after treatment with both 400 and 1200 r irradiation. This was followed by an increase within the next 12 hours. After this the conjugation capacity diminished greatly so that the decrease was 58% with the 400 r dose and 71% with the 1200 r dose. The conjugation capacity approcahed the control level within 8 days, and 20 and 30 days after the irradiation it was abovemore » the control level. After a slight initial decrease 12 hours after the treatment, the enzyme activity in beta -glucuronidase rose, being at its maximum 3 days after the irradiation. The increase was 50% with the 400 r dose and 37% with the 1200 r dose. After this the activity settled to the control level. (P.C.H.)« less
  • Cysteamine (CSH) and its close derivatives deplete immunoreactive somatostatin (SS) in rat organs. The effect of CSH is dose and time dependent and reversible. Structural requirements of the analogs are the presence of either -SH or -NH2 on a two- or three-carbon alkyl molecule; both radicals together increase, whereas insertion of carboxyl abolishes potency. The duodenal ulcerogenic potency of CSH derivatives is correlated significantly with their SS-depleting activity in the gastric mucosa. The mechanism of this action of CSH is poorly understood, but it is not caused by increased release, enhanced degradation of the peptide, or selective necrosis of SSmore » cells. It is likely that in the intracellular environment CSH causes a conformational change in the peptide that affects the antigenic and functional properties of SS.« less