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

Xenobiotica. 2011 Mar;41(3):212-25. doi: 10.3109/00498254.2010.532887. Epub 2010 Nov 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme System / metabolism
  • Environmental Pollutants / chemistry
  • Environmental Pollutants / metabolism*
  • Epoxy Compounds / metabolism*
  • Humans
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Photochemical Processes
  • Rats
  • Thioxanthenes / chemistry
  • Thioxanthenes / metabolism*

Substances

  • Environmental Pollutants
  • Epoxy Compounds
  • Thioxanthenes
  • isopropyl-9H-thioxanthen-9-one
  • Cytochrome P-450 Enzyme System