Thioguanine-induced adrenocortical necrosis and its prevention by hypophysectomy in the rat. Light and electron microscopic study

Szabó, Sándor; Kovács, Kálmán; Horváth, Éva; Szabó, Dorottya; Hüttner, I; Garg, Bindu; Tuchweber, Béatriz

doi:10.1016/0014-4800(77)90074-0

Cited by 10 publications

(5 citation statements)

References 18 publications

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“…Namely, among the most potent duodenal ulcerogens, cysteamine and cystamine do produce adrenal damage; propionitrile and n-butyronitrile are virtually devoid of this action (7)(8)(9)(10)(11). These data also suggested, like the present analysis, that sulfhydryl and double bonds enhance the adrenocorticolytic action of chemicals (10,12,13).…”

Section: Implications For Pathogenesis Of Organ Lesions and Drug Designsupporting

confidence: 89%

“…Acrylonitrile, for example, is a weak duodenal ulcerogen but a very potent adrenocorticolytic chemical (12). Propionitrile exerts the opposite effects, while cysteamine is very potent in producing both duodenal ulcer and adrenal necrosis in the rat (6,10,13).…”

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confidence: 99%

“…Propionitrile exerts the opposite effects, while cysteamine is very potent in producing both duodenal ulcer and adrenal necrosis in the rat (6,10,13). Nevertheless, acrylonitrile and cysteamine may also serve as animal models of human adrenocortical insufficiency or hemorrhagic adrenocortical necrosis, otherwise known as adrenal apoplexy or Waterhouse-Friderichsen syndrome (12,13). Structure-activity studies with derivatives of propionitrile and cysteamine thus revealed not only appropriate animal models of duodenal ulcer and adrenal necrosis but also demonstrated that these lesions can be induced in experimental animals in a rational and predictable fashion (10,11).…”

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confidence: 99%

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Predicting chemically induced duodenal ulcer and adrenal necrosis with classification trees.

Giampaolo¹,

Gray²,

Olshen³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Binary tree-structured statistical classification algorithms and properties of 56 model alkyl nucleophiles were brought to bear on two problems of experimental pharmacology and toxicology. Each rat of a learning sample of 745 was administered one compound and autopsied to determine the presence of duodenal ulcer or adrenal hemorrhagic necrosis. The cited statistical classification schemes were then applied to these outcomes and 67 features of the compounds to ascertain those characteristics that are associated with biologic activity. For predicting duodenal ulceration, dipole moment, melting point, and solubility in octanol are particularly important, while for predicting adrenal necrosis, important features include the number of sulfhydryl groups and double bonds. These methods may constitute inexpensive but powerful ways to screen untested compounds for possible organ-specific toxicity. Mechanisms for the etiology and pathogenesis of the duodenal and adrenal lesions are suggested, as are additional avenues for drug design.Duodenal ulcer disease is a frequent and poorly understood disorder. Quantitative structure-activity studies of chemical duodenal ulcerogens are of great interest, since they can yield toxicologic information regarding the etiology and mechanisms of ulceration, suggest pharmacologic approaches, and ultimately bear upon clinical practice. Duodenal ulcers are 2-4 times more frequent than gastric ulcers in humans, yet much more is known about the pathophysiology of gastric mucosal lesions than about duodenal ulceration (1). This is due in part to the lack of availability of requisite animal models of duodenal ulcer disease.It has long been known that gastric ulcers and erosions can be induced easily in both humans and laboratory animals by a variety of chemicals (in toxic doses) that elicit stress response. Selye (2) was the first to recognize that during stress a common set of pathogenetic mechanisms link many of the different etiologic factors. Until recently, animal models of duodenal ulcers were scarce (1). Available methods, such as pantothenic acid deficiency in certain strains of rats, the prolonged infusion of secretagogues, or the local application of acetic acid on the duodenum, were cumbersome and typically produced a low yield of duodenal ulcers (1, 3, 4). The first rapidly developing experimental duodenal ulcer was produced by subcutaneous administration of propionitrile, which consistently induced solitary, and often perforating, duodenal ulcers in 80%o of rats (5). Subsequently, cysteamine was also found to produce duodenal ulcers in rats (6). This model offered advantages since the ulcers developed more rapidly and consistently than after propionitrile administration, and only one to three doses were required. Since then, several other compounds have been shown to be duodenal ulcerogens, including 3,4-toluenediamine (7), 3,4-toluenedithiol, and n-butyronitrile (8, 9). The latter two chemicals were discovered during our initial structure-activity studies, which revealed th...

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Section: Implications For Pathogenesis Of Organ Lesions and Drug Designsupporting

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Predicting chemically induced duodenal ulcer and adrenal necrosis with classification trees.

Giampaolo¹,

Gray²,

Olshen³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…Some aliphatic nitriles such as butyronitrile, acetonitrile, and propionitrile were proved to exert their toxicity through cyanide liberation, leading to the inhibition of hepatic and brain cytochrome c oxidase in rat [1], and methacrylonitrile-related non-neoplastic lesions were seen in the nose and livers of rats [2]. In addition, animal studies have indicated additional effects of nitriles poisoning, including the development of duodenal ulcers, nuclear changes in neurons and satellite spinal ganglia, thyroid hyperemia and hyperplasia, neurogenic bladder dysfunction and adrenal apoplexy [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Comparative investigations of genotoxic activity of five nitriles in the comet assay and the Ames test

Hseu

Chen

et al. 2009

Journal of Hazardous Materials

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“…The experimental diabetes (damage to the islet cells of the pancreas) produced by alloxan or streptozotocin (1), the parathyroid necrosis induced by asparaginase (2), the hexadimethrine bromide-caused necrosis of the pituitary gland and adrenal cortex (3), as well as the hemorrhage or necrosis in the adrenal gland following the administration of 7,12-dimethylbenz(a)anthracene (4), acrylonitrile (5), or thioguanine (6) are examples of the few rare endocrine lesions related to chemicals. Although extensive studies have been undertaken on the relations between structure and activity of antithyroid drugs (that is, inhibitors in vari-ous steps of thyroid hormone synthesis) (7) and on the goitrogenic action of chemicals (8) only radioactive iodine has been available to induce necrosis in the thyroid gland.…”

mentioning

confidence: 99%

Pyrazole-Induced Thyroid Necrosis: A Distinct Organ Lesion

Szabó

Horbath

Kovács

et al. 1978

Science

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One oral dose of pyrazole caused necrosis of rat thyroid follicular epithelial cells but spared the parafollicular (C) cells and the parathyroid glands. Serum thyroxine (T4) and triiodothyronine (T3) were significantly decreased on day 3 after pyrazole administration and were immeasurable on day 5. At day 5 the thyroid was enlarged and the concentration of thyroid-stimulating hormone in the serum was increased, indicating an appropriate pituitary response to a primary lesion in the thyroid. Doses of pyrazole which produced no morphologic change in the thyroids also significantly depressed the concentrations of T4 and T3 in the serum.

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Thioguanine-induced adrenocortical necrosis and its prevention by hypophysectomy in the rat. Light and electron microscopic study

Cited by 10 publications

References 18 publications

Predicting chemically induced duodenal ulcer and adrenal necrosis with classification trees.

Predicting chemically induced duodenal ulcer and adrenal necrosis with classification trees.

Comparative investigations of genotoxic activity of five nitriles in the comet assay and the Ames test

Pyrazole-Induced Thyroid Necrosis: A Distinct Organ Lesion

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