The metabolism of acetamidothiazoles in the rat. 2-Acetamido-4-chloromethylthiazole

Chatfield, David H.; Hunter, W. H.

doi:10.1042/bj1340879

Cited by 27 publications

(4 citation statements)

References 9 publications

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“…The sulfur analogue may not isomerize to the analogous methoxy derivative, so that the stable sulfoxide is detected (Figure 7). This is similar to the finding that the antiinflammatory drug 2-acetamido-4-(chloromethyl)thiazole is reported to be excreted as a stable methyl sulfoxide (19).…”

Section: Discussionsupporting

confidence: 87%

Microsomal metabolism of 2-(methylseleno)benzanilide

Nj¹,

Terlinden²,

Fischer³

et al. 1990

Chem. Res. Toxicol.

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2-(Methylseleno)benzanilide, a metabolite of ebselen, was oxidatively demethylated by rat liver microsomes to regenerate the parent compound, ebselen. The rate of this novel reaction exceeds that of ring hydroxylation, and it was inhibitable with metyrapone. The sulfur analogue, 2-(methylthio)benzanilide, was oxidized to the corresponding sulfoxide. The regeneration of ebselen from 2-(methylseleno)benzalide is suggested to result from an intermediate selenoxide and hydrolysis with formation of methanol, since only very small amounts of labeled formaldehyde were detected in incubations using 2-[(14C)methylseleno]benzanilide. In an analogous reaction, 2-(benzylseleno)benzaldehyde yielded ebselen upon oxidation with hydrogen peroxide and, as detected by gas-liquid chromatography, benzyl alcohol.

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Section: Discussionsupporting

confidence: 87%

Microsomal metabolism of 2-(methylseleno)benzanilide

Nj¹,

Terlinden²,

Fischer³

et al. 1990

Chem. Res. Toxicol.

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“…However, in 1965, Colucci and Buyske showed that benzothiazole-2-sulfonamide is converted in rats, rabbits and dogs in part to 2-mercaptobenzothiazine in which the sulfur of the mercaptan moiety is derived from GSH. Later, Chatfield and Hunter (1973) showed that 2-acetamido-4-chloromethylthiazole is converted in rats to 2-acetamido-4-methylthiomethylthiazole in part through the mercapturate pathway. Earlier, Anderson and Schultze (1965) showed that bovine liver and kidney extracts contain a “C-S” lyase that converts S -(1,2-dichlorovinyl)-L-cysteine (DCVC, the cysteine S -conjugate of trichloroethylene) to pyruvate, ammonia and a reactive chlorine-containing fragment.…”

Section: Discovery Of Cysteine S-conjugate β-Lyases – the Thiomethyl mentioning

confidence: 99%

Cysteine S-conjugate β-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents

et al. 2010

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SummaryCysteine S-conjugate β-lyases are pyridoxal 5′-phosphate-containing enzymes that catalyze β-elimination reactions with cysteine S-conjugates that possess a good leaving group in the β-position. The end products are aminoacrylate and a sulfur-containing fragment. The aminoacrylate tautomerizes and hydrolyzes to pyruvate and ammonia. The mammalian cysteine S-conjugate β-lyases thus far identified are enzymes involved in amino acid metabolism that catalyze β-lyase reactions as non-physiological side reactions. Most are aminotransferases. In some cases the lyase is inactivated by reaction products. The cysteine S-conjugate β-lyases are of much interest to toxicologists because they play an important key role in the bioactivation (toxication) of halogenated alkenes, some of which are produced on an industrial scale and are environmental contaminants. The cysteine S-conjugate β-lyases have been reviewed in this journal previously . Here we focus on more recent findings regarding: 1) the identification of enzymes associated with high-M r cysteine S-conjugate β-lyases in the cytosolic and mitochondrial fractions of rat liver and kidney; 2) the mechanism of syncatalytic inactivation of rat liver mitochondrial aspartate aminotransferase by the nephrotoxic β-lyase substrate S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (the cysteine S-conjugate of tetrafluoroethylene); 3) toxicant channeling of reactive fragments from the active site of mitochondrial aspartate aminotransferase to susceptible proteins in the mitochondria; 4) the involvement of cysteine S-conjugate β-lyases in the metabolism/bioactivation of drugs and natural products; and 5) the role of cysteine S-conjugate β-lyases in the metabolism of selenocysteine Se-conjugates. This review emphasizes the fact that the cysteine S-conjugate β-lyases are biologically more important than hitherto appreciated.

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“…This metabolite was considered to be generated by scission of the methylaminothiazole ring, as reported for other thiazole derivatives which yielded the thioamides (13)(14)(15)(16). The mechanism of metabolic ring-opening of the thiazole of SM-8849 is now under investigation with toxicological interest, for an anti-thyroid action of thiourylene derivatives is well-known (17).…”

Section: L-5512mentioning

confidence: 99%

Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849) in rats

Yabuki

Shimakura

Ito

et al. 1997

European Journal of Drug Metabolism and Pharmacokinetics

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Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849), a novel immunomodulatory agent, in rats was investigated. By co-chromatography with authentic samples, desmethylated (SM-8800) p-hydroxylated (SL-5512) and desmethylated-p-hydroxylated SM-8849 (SL-5515) were detected in the bile. Thermospray mass spectrometry (TSP-MS) analysis of five metabolites isolated from the bile revealed molecular ions of both conjugates (glucuronides and a sulfate) and their aglycones. Aglycone structures were determined by comparison of their product spectra with those of authentic standards. Further analyses of conjugation sites were carried out by 1H-NMR including differential NOE. As a result, the sulfate of SL-5515 (5515-S), the N-glucuronides of SL-5512 and SM-8849 (5512-NG and 8849-NG, respectively), the glucuronide of SL-5512 (5512-G) and the O-glucuronide of 4-hydroxy-3-methoxy-SM-8849 (CatOMe-OG) were identified. In addition, N-methylthiouras was identified in urine by LC/MS/MS.

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The metabolism of acetamidothiazoles in the rat. 2-Acetamido-4-chloromethylthiazole

Cited by 27 publications

References 9 publications

Microsomal metabolism of 2-(methylseleno)benzanilide

Microsomal metabolism of 2-(methylseleno)benzanilide

Cysteine S-conjugate β-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents

Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849) in rats

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