title: Prediction of the metabolic clearance of benzophenone-2, and its interaction with isoeugenol and coumarin using cryopreserved human hepatocytes in primary culture.
abstract: Benzophenone-2 (BP2) is widely used as a UV screen in both industrial products and cosmetic formulations, where it is frequently found associated with fragrance compounds, such as isoeugenol and coumarin. BP2 is now recognized as an endocrine disruptor, but to date, no information has been reported on its fate in humans. The intrinsic clearance (Clint) and metabolic interactions of BP2 were explored using cryopreserved human hepatocytes in primary cultures. In vitro kinetic experiments were performed to estimate the Michaelis-Menten parameters. The substrate depletion method demonstrated that isoeugenol was cleared more rapidly than BP2 or coumarin (Clint = 259, 94.7 and 0.40 μl/min/10(6) cells respectively). This vitro model was also used to study the metabolic interactions between BP2 and isoeugenol and coumarin. Coumarin exerted no effects on either isoeugenol or BP2 metabolism, because of its independent metabolic pathway (CYP2A6). Isoeugenol appeared to be a potent competitive substrate inhibitor of BP2 metabolism, equivalent to the specific UGT1A1 substrate: estradiol. Despite the fact that inhibition of UGT by xenobiotics is not usually considered to be a major concern, the involvement of UGT1A1 in BP2 metabolism may have pharmacokinetic and pharmacological consequences, due to the its polymorphisms in humans and its pure estrogenic effect.
authors.affiliation: UMR 1331 TOXALIM (Research Centre in Food Toxicology), Institut National de la Recherche Agronomique (INRA), Laboratory of Xenobiotic's Cellular and Molecular Toxicology, 400 route des Chappes, BP 167, 06903 Sophia-Antipolis Cedex, France. Electronic address: desousa@sophia.inra.fr.
authors.forename: Georges
authors.initials: G
authors.lastname: de Sousa
authors.affiliation: INERIS Models for Ecotoxicology and Toxicology Unit, Verneuil-en-Halatte, 60550, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Teng
authors.affiliation: UMR 1331 TOXALIM (Research Centre in Food Toxicology), Institut National de la Recherche Agronomique (INRA), Laboratory of Xenobiotic's Cellular and Molecular Toxicology, 400 route des Chappes, BP 167, 06903 Sophia-Antipolis Cedex, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Salle-Siri
authors.affiliation: INERIS Models for Ecotoxicology and Toxicology Unit, Verneuil-en-Halatte, 60550, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pery
authors.affiliation: UMR 1331 TOXALIM (Research Centre in Food Toxicology), Institut National de la Recherche Agronomique (INRA), Laboratory of Xenobiotic's Cellular and Molecular Toxicology, 400 route des Chappes, BP 167, 06903 Sophia-Antipolis Cedex, France. Electronic address: rahmani@sophia.inra.fr.
authors.forename: Roger
authors.initials: R
authors.lastname: Rahmani
mesh_terms: D001577:Benzophenones / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D003374:Coumarins / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005054:Eugenol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure
chemical_list: D001577:Benzophenones; D003374:Coumarins; D005054:Eugenol; C036643:isoeugenol; C030123:coumarin; C035476:2,2',4,4'-tetrahydroxybenzophenone
keywords: Environmental chemical; Human hepatocytes; Metabolic interaction; Metabolism