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. 2006 Jun;19(6):818-27.
doi: 10.1021/tx0600402.

A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse

Sarbani Giri  1 , Jeffrey R Idle, Chi Chen, T Mark Zabriskie, Kristopher W Krausz, Frank J Gonzalez
Affiliations

A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse

Sarbani Giri et al. Chem Res Toxicol. 2006 Jun.

Abstract

The areca alkaloids comprise arecoline, arecaidine, guvacoline, and guvacine. Approximately 600 million users of areca nut products, for example, betel quid chewers, are exposed to these alkaloids, principally arecoline and arecaidine. Metabolism of arecoline (20 mg/kg p.o. and i.p.) and arecaidine (20 mg/kg p.o. and i.p.) was investigated in the mouse using a metabolomic approach employing ultra-performance liquid chromatography-time-of-flight mass spectrometric analysis of urines. Eleven metabolites of arecoline were identified, including arecaidine, arecoline N-oxide, arecaidine N-oxide, N-methylnipecotic acid, N-methylnipecotylglycine, arecaidinylglycine, arecaidinylglycerol, arecaidine mercapturic acid, arecoline mercapturic acid, and arecoline N-oxide mercapturic acid, together with nine unidentified metabolites. Arecaidine shared six of these metabolites with arecoline. Unchanged arecoline comprised 0.3-0.4%, arecaidine 7.1-13.1%, arecoline N-oxide 7.4-19.0%, and N-methylnipecotic acid 13.5-30.3% of the dose excreted in 0-12 h urine after arecoline administration. Unchanged arecaidine comprised 15.1-23.0%, and N-methylnipecotic acid 14.8%-37.7% of the dose excreted in 0-12 h urine after arecaidine administration. The major metabolite of both arecoline and arecaidine, N-methylnipecotic acid, is a novel metabolite arising from carbon-carbon double-bond reduction. Another unusual metabolite found was the monoacylglyceride of arecaidine. What role, if any, that is played by these uncommon metabolites in the toxicology of arecoline and arecaidine is not known. However, the enhanced understanding of the metabolic transformation of arecoline and arecaidine should contribute to further research into the clinical toxicology of the areca alkaloids.

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Figures

Figure 1
Figure 1
Structures of the areca alkaloids found in areca nut. (I), arecoline; (II), arecaidine; (XII), guvacoline; (XIII), guvacine.
Figure 2
Figure 2
Multivariate data analysis of urinary arecoline metabolites. (A) Separation of control and arecoline treated (20 mg/kg p.o.) mouse urine samples in a PLS-DA scores plot (PLS-DA1/PLS-DA2). (B) Loadings plot of variables generated by PLS-DA. This loading plot represents the relationship between variables (ions) and observation groups (control and arecoline treated) with regard to the first and second components (PLS-DA1/ PLS-DA2) present in (A). W*C represents the combination of the weights of variables and the principal components.
Figure 3
Figure 3
Identification of N-methylnipecotic acid as a metabolite of arecoline by LC–MS/MS. (A) Single-ion chromatogram (m/z = 144.1) of urine from an untreated mouse, showing a single major peak eluting at 0.30 min in 20 mM ammonium formate (pH 6.4). The positive-ion MS/MS spectrum shows a [M +H]+ion at 144.102 m/z and a fragment ion at 84.081 m/z. (B) Single-ion chromatogram (m/z = 144.1) of urine from a mouse treated with arecoline (20 mg/kg p.o.), showing a single peak eluting at 0.30 min in 20 mM ammonium formate (pH 6.4). The positive-ion MS/MS spectrum shows a protonated ion at 144.102 m/z and fragment ions at 98.098 and 126.095 m/z. (C) Single-ion chromatogram (m/z = 144.1) of a 10 μM aqueous solution of N-methylnipecotic acid, showing its chemical structure and a single peak eluting at 0.30 min in 20 mM ammonium formate (pH 6.4). The positive-ion MS/MS spectrum shows a protonated ion at 144.103 m/z and fragment ions at 98.097 and 126.092 m/z. (D) Single-ion chromatogram (m/z = 144.1) of a 10 μM aqueous solution of N-methylpipecolic acid, showing its chemical structure and a single peak eluting at 0.38 min in 20 mM ammonium formate (pH 6.4). The positive-ion MS/MS spectrum shows a protonated ion at 144.103 m/z and a large fragment ion at 98.096 m/z.
Figure 4
Figure 4
MS/MS analysis of arecoline mercapturic acid. (A) MS/ MS spectrum of the urinary peak eluting at 1.22–1.23 min with a mass of 319.1 m/z. (B) MS/MS spectrum of synthetic arecoline mercapturic acid that eluted at 1.22–1.23 min with a mass of 319.1 m/z.
Figure 5
Figure 5
The metabolic map of arecoline and arecaidine in the mouse. Identity of urinary metabolites is as follows: arecoline (I), arecaidine (II), arecoline N-oxide (III), arecaidine N-oxide (IV), N-methylnipecotic acid (V), N-methylnipecotylglycine (VI), arecaidinylglycine (VII), arecaidinylglycerol (VIII), arecaidine mercapturic acid (IX), arecoline mercapturic acid (X), and arecoline N-oxide mercapturic acid (XI).
Figure 6
Figure 6
Relative approximate percentages of each urinary metabolite of arecoline and arecaidine in the mouse. (A) Urinary metabolite profile for arecoline (20 mg/kg p.o. and i.p.) in the mouse (for key to metabolites, see Figure 5). (B) Urinary metabolite profile for arecaidine (20 mg/kg p.o. and i.p.) in the mouse (for key to metabolites, see Figure 5).
Figure 7
Figure 7
Calibration curves for authentic arecoline metabolites. Data are mean ± SD for duplicates. (A) Arecoline, linear from 0 to 25 μM, r2 = 0.997. (B) Arecaidine, linear from 0 to 25 μM, r2 = 0.992. (C) Arecoline N-oxide, linear from 0 to 100 μM, r2 = 0.998. (D) N-Methylnipecotic acid, linear from 0 to 50 μM, r2 = 0.992.
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