title: In vitro metabolism study of 2-isopropyl-9H-thioxanthen-9-one (2-ITX) in rat and human: evidence for the formation of an epoxide metabolite.
abstract: 1. 2-Isopropyl-9H-thioxanthen-9-one (2-ITX) is one of the most extensively used photoinitiators in inks found in paper and/or packaging materials for foodstuffs. Recently, traces of 2-ITX as a contaminant were discovered in baby milk and other foodstuffs at a level sufficient to pose a risk to human health. However, little is known about the toxicological profile of 2-ITX. 2. The high lipophilicity of this substance would suggest that it could be a good substrate for hepatic metabolizing enzymes and that these metabolites could have a role in the toxicological properties of 2-ITX. 3. The metabolism of 2-ITX, using both rat and human subcellular preparations, was studied and has resulted in the formation of eight polar metabolites (M1-M8) as revealed in the liquid chromatograpy/ultraviolet (LC/UV) and liquid chromatograpy/mass spectrometry (LC/MS) analyses. Their structures highlight a marked regioselectivity in the metabolism of 2-ITX; it is directed mainly toward the isopropyl moiety and the sulfur atom. 4. The unsaturated metabolite 6 causes the formation of a reactive epoxide metabolite 7. This finding was supported by identification in microsomal incubations of 1,2-diol metabolite 8 arising from the epoxide by hydrolysis and it was validated by incubating in the same conditions the synthetic epoxide 7: the formation of metabolite 8 was again observed. 5. On the basis of these data, we propose that the metabolite 6 could be included in toxicological studies of 2-ITX.
authors.affiliation: Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and Drug and Food Biotechnology Center, Università degli Studi del Piemonte Orientale A. Avogadro, Largo Donegani 2, 28100 Novara, Italy. silvio.aprile@pharm.unipmn.it
authors.forename: Silvio
authors.initials: S
authors.lastname: Aprile
authors.forename: Erika
authors.initials: E
authors.lastname: Del Grosso
authors.forename: Giorgio
authors.initials: G
authors.lastname: Grosa
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004785:Environmental Pollutants / Q000737:chemistry / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D055668:Photochemical Processes; D051381:Rats; D013892:Thioxanthenes / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004785:Environmental Pollutants; D004852:Epoxy Compounds; D013892:Thioxanthenes; C518329:isopropyl-9H-thioxanthen-9-one; D003577:Cytochrome P-450 Enzyme System