Chemical and enzymic oxidation of benzimidazoline-2-thiones: a dichotomy in the mechanism of peroxidase inhibition

Doerge, Daniel R.; Decker, Carolin; Takazawa, Richard S.

doi:10.1021/bi00052a009

Cited by 30 publications

(23 citation statements)

References 26 publications

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“…In addition, the oxidation of guaiacol can be used as an indicator of thyroid peroxidase activity (327). All chemicals that inhibit the iodination reaction also inhibit the coupling reaction (38). The coupling reaction can be assayed using either human low iodine thyroglobulin, preiodinated casein, or guaiacol as substrates.…”

Section: Thyroid Function and Regulationmentioning

confidence: 99%

Screening methods for thyroid hormone disruptors.

DeVito

Biegel

Brouwer

et al. 1999

Environ Health Perspect

164

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The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen.

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Section: Thyroid Function and Regulationmentioning

confidence: 99%

Screening methods for thyroid hormone disruptors.

DeVito

Biegel

Brouwer

et al. 1999

Environ Health Perspect

164

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“…The imidazole-2-thiones have also shown a wide range of biological activities, having antitumor (Iradyan et al, 1987), antiulcer (Tsuji et al, 1989), anti-inflammatory (Selig et al, 2011;Tsuji et al, 1989), antiarthritic, analgesic (Sharpe et al, 1985), antihyperthyroid (Doerge et al, 1993), tuberculostatic (Trzhtsinskaya et al, 1992), antibacterial, antifungal and insecticidal activity (Saeed and Batool, 2007). They were also shown to possess anti-HIV activity, by showing non-nucleoside reverse transcriptase inhibition (Yasser et al, 2003) and human cytosolic phospholipase A2 activity having a role in preventing inflammation (Makita et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro antiplatelet aggregation screening of novel fluorinated diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate derivatives

et al. 2014

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Seven fluorinated derivatives of diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate (a-g) as well as a nitro and chloro derivative (h-i) were prepared in five steps from glycine, ethyl formate, diethyl oxalate, potassium thiocyanate and substituted benzyl bromides. The structures of the synthesised compounds were elucidated and verified using 1 H, 13 C and 2D NMR spectroscopy where appropriate. The synthesised compounds exhibited concentration dependent antiplatelet aggregation activity on both the thrombin and ADP-induced platelet aggregation. The 4-nitro and 4-fluoro compounds exhibited the highest activity from the compounds tested, with IC 50 values of 1.06 and 1.20 mM for the thrombininduced assay and 18.57 and 12.91 mM in the ADP-induced platelet aggregation assay respectively. Three of the compounds, the 3 00 ,4 00 -difluoro (6c), 4 00 -nitro (6h) and 3 00 -chloro (6i) derivatives, have reasonable activity in both of the assays and could have potential as broad spectrum antiplatelet inhibitors. With the exception of 6c, the fluoro derivatives were not as active as the nitro and chloro compounds.

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“…These data suggest that the metabolic desulfuration of MBI was reduced by repeated dosing. Although the mode of the desulfuration of these thioureylenes was not investigated in the present study, it has been shown that desulfuration of methimazole by flavin-containing monooxygenase (FMO) and LPX involves an oxidative process via sulfenic acid and sulfinic acid formation (Doerge et al 1993;Parkinson 1996).…”

Section: Mbi Versus the Mmbi MIXmentioning

confidence: 95%

Comparative toxicokinetic/toxicodynamic study of rubber antioxidants, 2-mercaptobenzimidazole and its methyl substituted derivatives, by repeated oral administration in rats

Sakemi

Ito

Umemura

et al. 2002

Archives of Toxicology

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2-Mercaptobenzimidazole (MBI), a rubber antioxidant, is known to exhibit potent thyroid toxicity in rats, whereas its methylated derivatives are much less toxic. To characterize this methyl-substituent effect on the thyroid toxicity of MBI, comparative toxicokinetic analyses have been conducted in the present study. MBI and the MMBIs [4-methylated MBI (4-MMBI) and 5-methylated MBI (5-MMBI), and a 1:1 mixture of these 4- and 5-methylated isomers (MMBI mix)] suspended in corn oil were repeatedly administered (at 0.3-0.6 mmol/kg) to male Wistar rats by gavage once daily for 2 weeks. After the first and last administrations, blood and urine samples were collected, and the levels of unchanged compounds and their desulfurated metabolites were determined by high performance liquid chromatography. After repeated oral administration (roa), the C(max) and area under concentration-time curve (AUC) of MBI were markedly increased, while the MMBIs essentially were cleared from the blood within 10 h. After roa, the C(max) and AUC of 4-MMBI decreased markedly, suggesting metabolic enzyme induction. However, the toxicokinetic parameters of 5-MMBI were not markedly altered by roa. The inhibitory potencies (IC(50)) against lactoperoxidase of MBI, 4-MMBI, and 5-MMBI were 20.6 micro M, 45.6 micro M and 31.6 micro M, respectively. Thus, we suggest that the marked decrease of thyroid toxicity by methyl substitution of MBI is caused mainly by a decrease in systemic exposure to the compounds and partly by a decrease in inhibition of thyroid hormone synthesis.

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Chemical and enzymic oxidation of benzimidazoline-2-thiones: a dichotomy in the mechanism of peroxidase inhibition

Cited by 30 publications

References 26 publications

Screening methods for thyroid hormone disruptors.

Screening methods for thyroid hormone disruptors.

Synthesis and in vitro antiplatelet aggregation screening of novel fluorinated diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate derivatives

Comparative toxicokinetic/toxicodynamic study of rubber antioxidants, 2-mercaptobenzimidazole and its methyl substituted derivatives, by repeated oral administration in rats

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