Metabolism of triallate in Sprague-Dawley rats.  3.  In vitro metabolic pathways

Hackett, Amy G.; Kotyk, John J.; Fujiwara, Hideji; Logusch, Eugene W.

doi:10.1021/jf00025a030

Cited by 8 publications

(7 citation statements)

References 17 publications

(31 reference statements)

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“…This mechanism was proposed for the TZD ring opening of troglitazone by Kassahun et al (2001). A similar mechanism was also proposed by Hackett et al (1993) and Nadeau et al (1993) for the metabolism of the herbicide, triallate. Direct oxidation of M22 to give M7, although possible, was not detected when M22 was incubated with NADPH-fortified liver microsomes.…”

Section: Discussionsupporting

confidence: 62%

IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL)-PHENYL] METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. II. IDENTIFICATION OF METABOLITES BY LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY

Liu¹,

Karanam

Doss³

et al. 2004

Drug Metab Dispos

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The in vitro metabolism of MK-0767 [(؎)-5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxy-N-[[(4-trifluoromethyl)-phenyl] methyl]benzamide], a novel 2,4-thiazolidinedione (TZD)-containing peroxisome proliferator-activated receptor ␣/␥ agonist, was studied in rat, dog, monkey, and human liver microsomes and hepatocytes, as well as in recombinant human CYP3A4-containing microsomes. Twenty-two metabolites (some at trace levels) were detected by liquid chromatography-tandem mass spectrometry analysis. All appeared to be phase I metabolites except for a glucuronide conjugate of a hydroxylated metabolite that was detected at trace levels. A constant neutral loss scan experiment performed on a triple quadrupole mass spectrometer proved to be very useful for resolving the metabolites from endogenous compounds. It was observed that the initial site of metabolism of MK-0767 was at the TZD ring leading to two major metabolites, namely the 5-hydroxy-TZD metabolite (M24) and the mercapto metabolite (M22). The latter was formed via the cleavage of the TZD ring with the elimination of the carbonyl adjacent to the sulfur atom. The structure of M24 was established by accurate mass measurements and NMR analysis. This hydroxy-TZD metabolite might represent an important precursor for a group of metabolites formed by TZD ring opening and subsequent loss of the sulfur moiety. The mercapto metabolite, on the other hand, is probably the key precursor for the TZD ring-opened metabolites with retention of the sulfur, even though the detailed mechanism of the ring scission remains to be characterized. From these studies, it was concluded that the TZD ring was the major site of metabolism of MK-0767. All the metabolites produced in vitro from human preparations were detected in the corresponding preparations from the nonclinical species.

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Section: Discussionsupporting

confidence: 62%

IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL)-PHENYL] METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. II. IDENTIFICATION OF METABOLITES BY LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY

Liu¹,

Karanam

Doss³

et al. 2004

Drug Metab Dispos

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“…We also describe separate feeding experiments, using radiolabeled metabolite intermediates, which allowed us to delineate the pathways of triallate metabolism in rats. The following paper (Hackett et al, 1993) presents an investigation of triallate in vitro metabolism using rat liver enzymes and provides mechanistic details for the pathways of triallate breakdown. Several other thiocarbamate animal metabolism studies have been reported (Chen et al, 1979; Debaun et al, 1978;Hubbell and Casida, 1977; Casida et al, 1975), although little information on in vivo triallate metabolism has been available (Marsden and Casida, 1982).…”

Section: Introductionmentioning

confidence: 99%

Metabolism of triallate in Sprague-Dawley rats. 2. Identification and quantitation of excreted metabolites

Nadeau¹,

Chott²,

Fujiwara³

et al. 1993

J. Agric. Food Chem.

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Triallate was administered orally to Sprague-Dawley rats. Twelve excreted metabolites were identified, the most abundant being 2,3,3-trichloro-2-propenesulfinic acid. Five metabolites derived from 2,3,3-trichloro-2-propenethiol were identified in excreta, including a methyl sulfone mercapturate whose structure was confirmed by X-ray crystallography. Three 2-chloroacrylate metabolites were identified, including a 2-chloroacrylate mercapturate whose structure was confirmed by X-ray crystallography. 2,3,3-Trichloro-2-propenol and hydroxytriallate were also identified as metabolites. Dosing of radiolabeled thiol and sulfinic acid to separate animals resulted in excretion of only thiolderived metabolites in the urine of thiol-dosed rats, while sulfinic acid and sulfonic acid were excreted by sulfinic acid-dosed rats. Triallate metabolism in rats proceeds via three main pathways, i.e., S-oxidation leading to sulfur acids, S-oxidation/hydrolysis/reduction leading to thiol derivatives, and C-oxidation of the 2,3,3-trichloropropenethioI moiety. This study demonstrates that formation of readily excreted sulfur acids and thiol derivatives is the major route of triallate metabolism in rats.

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“…Kaufman (1967), de Lorenzo et al (1978), and Sandhu and Waters (1980) suggested that a metabolite carrying the trichloroallyl moeity is probably responsible for the positive results in the Ames test with S. typhimurium strains TA100 and TA1535. More recently, Hackett et al (1993) demonstrated that trichloroacrolein is formed in vitro when triallate is incubated with S9 mix (Figure 3). However, the lability of trichloroacrolein is such that it is mainly detected as a secondary metabolite (trichloroal-lyl alcohol) or as glutathione (GSH) metabolites when GSH is available.…”

Section: Mouse Micronucleus Assaymentioning

confidence: 90%

“…Metabolic pathway for triallate (Hackett et al 1993;Nadeau et al 1993). The star ( ) indicates the site of the radiolabel.…”

Section: Figurementioning

confidence: 99%

A Review of the Genotoxicity of Triallate

Healy

Kier²,

Broeckaert³

et al. 2003

Int J Toxicol

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Triallate is a selective herbicidal chemical used for control of wild oats in wheat. It has an extensive genotoxicity database that includes a variety of in vitro and in vivo studies. The chemical has produced mixed results in in vitro assay systems. It was genotoxic in bacterial mutation Ames assays, predominantly in Salmonella typhimurium strains TA100 and TA1535 in the presence of S9. Weaker responses have been observed in TA100 and TA1535 in the absence of S9. Mixed results have been observed in strain TA98, whereas no genotoxicity has been observed in strains TA1537 and TA1538. The presence and absence of S9 and its source seem to play a role in the bacterial response to the chemical. There have also been conflicting results in other test systems using other bacterial genera, yeast, and mammalian cells. Chromosome effects assays (sister-chromatid exchange and cytogenetics assays) have produced mixed results with S9 but no genotoxicity without S9. Triallate has not produced any genotoxicity in in vitro DNA damage or unscheduled DNA synthesis assays using EUE cells, human lymphocytes, and rat and mouse hepatocytes. In a series of in vivo genotoxicity assays (cytogenetics, micronucleus, dominant lethal, and unscheduled DNA synthesis), there has been no indication of any adverse genotoxic effect. Metabolism data indicate that the probable explanation for the differences observed between the in vitro studies with S9 and without S9 and between the in vitro and the in vivo studies is the production of a mutagenic intermediate in vitro at high doses of triallate is expected to be at most only transiently present in in vivo studies. The weight of evidence strongly suggests that triallate is not likely to exert mutagenic activity in vivo due to toxicokinetics and metabolic processes leading to detoxification.

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Metabolism of triallate in Sprague-Dawley rats. 3. In vitro metabolic pathways

Cited by 8 publications

References 17 publications

IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL)-PHENYL] METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. II. IDENTIFICATION OF METABOLITES BY LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY

IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL)-PHENYL] METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. II. IDENTIFICATION OF METABOLITES BY LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY

Metabolism of triallate in Sprague-Dawley rats. 2. Identification and quantitation of excreted metabolites

A Review of the Genotoxicity of Triallate

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