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Xenobiotica
the fate of foreign compounds in biological systems
Volume 36, 2006 - Issue 9
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Original

Transesterification of p-hydroxybenzoate esters (parabens) by human intestinal (Caco-2) cells

, , , , &
Pages 739-749 | Received 27 Dec 2005, Accepted 06 Apr 2006, Published online: 11 Aug 2009
 

Abstract

p-Hydroxybenzoate ester (paraben) preservatives are used in numerous orally administered products. The recognized route of metabolism for parabens is hydrolysis to p-hydroxybenzoic acid followed by conjugation and excretion. However, in the presence of alcohols, a presystemic transesterification pathway not previously reported for the human intestine can occur. Using human intestinal (Caco-2) cells, it was observed that hydrolysis of parabens to p-hydroxybenzoic acid is reduced markedly by ethanol concentrations that can occur in the human intestine, 0.25–0.5% (v/v). Ethanol concentrations of 1.0–2.5% (v/v) were optimal for transesterification to ethylparaben in Caco-2 cell homogenates. The kinetics of the transesterification reaction with regard to ethanol concentration (0–20%), time, pH (3–9), protein concentration (1–5 mg ml−1) and substrate concentration (6.25–200 µM) as well as the effects of different alcohols were studied. The Km and Vmax values for transesterification with ethanol for methyl, propyl, butyl, heptyl and octyl parabens were 449.7, 165.7, 86.1, 24.2 and 45.9 µM and 114.4, 37.5, 19.5, 7.5 and 7.6 µmol h−1 mg−1 Caco-2 cell protein, respectively. The Vmax values for transesterification of methylparaben with ethanol, propan-1-ol, butan-1-ol were 114.4, 5.1 and 4.9 µmol h−1 mg−1, respectively. Collectively, the kinetic data demonstrate that the enzyme responsible for the transesterification reaction has a preference for short-chain esters and represents the first report of transesterification in human intestinal cells. An implication of this mechanism is that alcohol-containing in vitro biosystems or protocols for the study of parabens disposition could generate transesterified artefacts. The clinical or toxicological implication is that, following co-ingestion of ester compounds with ethanol, transesterification could provide the basis for a previously unrecognized drug-alcohol interaction.

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