Identification of Metabolites of [1,2,3-¹³C]Propargyl Alcohol in Rat Urine by ¹³C NMR and Mass Spectrometry

Abstract

Little is known about the metabolism of acetylenic (C&tbd1;C) compounds commonly used in the formulation of pesticides. To better understand the in vivo reactivity of this bond, we examined the metabolism of propargyl alcohol (PA), 2-propyn-1-ol, used extensively in the chemical industry. [1,2,3-(13)C, 2,3-(14)C]PA was administered orally to male Sprague-Dawley rats. Approximately 56% of the dose was excreted in urine by 96 h. Major metabolites were characterized, directly, in the whole urine by one- and two-dimensional (13)C NMR. To determine the complete structures of metabolites of PA, rat urine was also subjected to TLC followed by purification of separated TLC bands on HPLC. The purified metabolites were identified by (13)C NMR and mass spectrometry and by comparison with available synthetic standards. The proposed metabolic pathway involves oxidation of propargyl alcohol to 2-propynoic acid and further detoxification via glutathione conjugation to yield as final products: 3, 3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol, 3-(carboxymethylthio)-2-propenoic acid, 3-(methylsulfinyl)-2-(methylthio)-2-propenoic acid, 3-[[2-(acetylamino)-2-carboxyethyl]thio]-3-[(2-amino-2-carboxyethyl)t hio]-1-propanol and 3-[[2-(acetylamino)-2-carboxyethyl]sulfinyl]-3-[2-(acetylamino)-2-car boxyethyl]thio]-1-propanol. These unique metabolites have not been reported previously and represent the first example of multiple glutathione additions to the carbon-carbon triple bond.

Disposition of propargyl alcohol in rat and mouse after intravenous, oral, dermal and inhalation exposure

“…One metabolite was analysed by LC/MS/MS. The fragmentation pattern for this metabolite is consistent with the structure of 3,3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol (Banijamali et al 1999), the result of the addition of two glutathione molecules across the carbon-carbon triple bond, possibly via Michael addition to an aldehyde intermediate.…”

“…Mass spectrometric analysis of peak Tsp using electrospray ionization resulted in the production of a prominent M+ H ion at m/z 383 ( gure 6A). Ion-neutral interactions between the non-charged molecule and [548][549][550] (acetylamino)-2-carboxyethyl)thio]-1-propanol, a urinary metabolite of PAL reported by Banijamali et al (1999). These daughter ions could be rationalized in part by the cleavage patterns shown in gure 6.…”

“…Furthermore, unlike allylic alcohols, PAL is a poor substrate for alcohol dehydrogenase (DeMaster et al 1994). The metabolism of [1,2,3-13 C 2,3-14 C]PAL by the male Sprague-Dawley rat has been reported by Banijamali et al (1999). About 56% of an orally administered dose (40 mg kg 1 ) was excreted in urine by 96 h after dose administration.…”

Prediction of acute toxicity in fish by using QSAR methods and chemical modes of action

“…Indeed, the metabolites of 16 have been studied 22 , and they result from oxidation of the alcohol leading to aldehyde and carboxylic acid. Thus, the metabolites of 16 should have the same chemical properties as acrolein.…”

A mechanism for the formation of bis‐glutathione conjugates of propargyl alcohol

“…To better understand the in vivo reactivity of propargyl alcohol, we previously investigated its metabolism in rats and mice 2. 3 In those studies, a mixture of 13 C‐ and 14 C‐propargyl alcohol was administered to rats and mice, and urinary metabolites were characterized by HPLC, mass spectrometry and NMR spectroscopy (Fig 1).…”