Identification of glutathione conjugates and mercapturic acids of 1,2-dibromopropane in female BALB/c mice by liquid chromatography-electrospray ionization tandem mass spectrometry

Abstract

Based on recent results that 1,2-dibromopropane (1,2-DBP) causes hepatotoxicity and immunotoxicity in female BALB/c mice as well as a reduction of hepatic glutathione levels, the possible formation of glutathione conjugates and mercapturic acids of 1,2-DBP was investigated in vivo in the present studies. The following four metabolites were identified in the liver at 12 h after treatment with 1,2-DBP, by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI/MS): M1, 2-hydroxypropylglutathione; M2, 2-oxopropylglutathione; M3, N-acetyl-S-(2-hydroxypropyl)-L-cysteine; and M4, N-acetyl-S-(2-oxopropyl)-L-cysteine. Ions of individual conjugates were observed at m/z 366, 364, 222 and 220, respectively. Characteristic product ions at m/z 237, 217, 204 and 202 for the identification of M1, M2, M3 and M4 were observed, respectively. In the sera isolated from the same animals, only mercapturic acids (M3 and M4) were observed by LC-ESI/MS. When female BALB/c mice were treated orally with 1,2-DBP at doses of 150, 300 and 600 mg kg(-1) once for 12 h, the production of glutathione conjugates and mercapturic acids in liver was apparently dose dependent, as were the concentrations of them in sera. When the production of metabolites from 1,2-DBP was investigated in liver following oral treatment with 600 mg kg(-1) 1,2-DBP for 6, 12, 24 and 48 h, metabolite concentrations were greatest at the first time point (6 h). The results explain the authors' previous studies that oral treatment with 1,2-DBP reduces the hepatic content of glutathione.

Role of Metabolism In 1-Bromopropane-Induced Hepatotoxicity in Mice

“…Members of this chemical class have also been employed as pesticides. Currently, 1-bromopropane (1-BP) is widely used as substitute for chlorofluorocarbons that destroy the ozone layer, as a cleaning agent or adhesive solvent in workplaces, because of the lower ozone-depleting potency, high volatility, and nonflammability (Låg et al, 1991;Lee et al, 2005a). The quantity of halopropanes being used has been increased in many situations.…”

Hepatotoxic and Immunotoxic Effects produced by 1,3‐Dibromopropane and Its Conjugation with Glutathione in Female BALB/c Mice

“…Mice treated orally with 1-BP showed enhanced hepatotoxicity and immunotoxicity following depletion of GSH in liver and spleen (Lee et al, 2005b). In addition, the hepatotoxicity and immunotoxicity produced by 2-BP and 1,2-DBP were also increased by the formation of conjugates with GSH (Kim et al, 2003;Lee et al, 2005a).…”

“…Many halide compounds, such as 1-bromopropane (1-BP), 1,2-dibromopropane (1,2-DBP), 2,3-dibromopropene (2,3-DBPE) and 1,2-dibromo-3-chloropropane (2,3-DBCP) are metabolized by conjugation with glutathione (GSH) (Barnsley et al, 1966;Burlinson et al,1982;Zoetemelk et al, 1986;TorneroVelez et al, 2004;Lee et al, 2005a).…”

Identification of glutathione conjugates of 1-bromopentane and its hepatotoxicity in female BALB/c mice

“…Short chain-halogenated alkanes are used industrially as chemical intermediates, extraction solvents, and co-polymer cross-linking agents. They are also used as cleaning agents or adhesive solvents in workplaces because of their lower ozone-depleting potency, high volatility, and non-flammability (Låg et al, 1991;Lee et al, 2005). However, toxicity information for 1-bromopentane (1-BPT) is limited.…”

“…In our previous studies, bromoalkane compounds such as 1-bromopropane (1-BP), 2-bromopropane (2-BP), 1,2-dibromopropane (1,2-DBP), and 1,3-dibromopropane could cause hepatotoxicity and immunotoxicity as well as depletion of GSH content by GSH conjugate formation in mice (Kim et al, 2003;Lee et al, 2005;Lee et al, 2007a;Lee et al, 2007b). Moreover, 1-BPT could be excreted in rat urine as several metabolites, including pentylmercapturic acid derivates (Grasse et al, 1970;Grasse and James, 1972).…”