title: Effects of the antimycobacterial compound 2-phenoxy-1-phenylethanone on rat hepatocytes and formation of metabolites.
abstract: BACKGROUND
  Neolignans are usually dimers formed by oxidative coupling of allyl and propenyl phenols, and the neolignan analogue, 2-phenoxy-1-phenylethanone (LS-2) is a promising antimycobacterial compound showing very weak cytotoxicity in mammalian cells and lack of acute toxicity in murine models.
  
  
  OBJECTIVE
  To investigate the mechanism of action of LS-2 in rat hepatocytes by evaluating the activity levels of enzymes related to oxidation status and drug-metabolizing activity.
  
  
  METHODS
  Hepatocytes were treated with LS-2 from 0.05 up to 1 mM, for 24 and 48 h, and reduced glutathione (GSH), lipid peroxidation and cytochrome P450 enzyme (CYP450) activity were assayed. A homologous series of phenoxazone ethers were used as substrates to measure the enzymatic profile. The biotransformation of LS-2 was studied in hepatocytes by gas chromatography-mass spectrometry (GC-MS) for detection and analysis of possible metabolites.
  
  
  RESULTS
  Hepatocytes treated with LS-2 up to 1 mM for 24 or 48 h did not induce the formation of GSH and lipid peroxidation. O-Dealkylation activities of the isoenzymes CYP4501A1, CYP4501A2, CYP4502B1 and CYP4502B2 were also not detected in the hepatocytes treated with LS-2 for 24 or 48 h.
  
  
  CONCLUSIONS
  The results indicate that LS-2 or its two detected metabolites, 2-phenoxy-1-phenylethanol and 2,4-(2-hydroxy-2-phenylethoxy)phenol, are not cytotoxic to rat hepatocytes. These compounds maintain a balance between the production of pro-oxidant agents and their respective antioxidant systems. The data show that enzymes related to oxidation status and drug-metabolizing activities are not involved in the mechanism of action of LS-2.
authors.affiliation: Laboratório de Bioquímica e Biofísica, Instituto Butantan, São Paulo, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Rodrigues Coutinho
authors.forename: Luiz Alberto Beraldo
authors.initials: LA
authors.lastname: de Moraes
authors.forename: Lauro Euclides Soares
authors.initials: LE
authors.lastname: Barata
authors.forename: Ana Olívia
authors.initials: AO
authors.lastname: de Souza
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000975:Antioxidants / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D017705:Lignans / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: C561330:2-phenoxy-1-phenylethanone; D000900:Anti-Bacterial Agents; D000975:Antioxidants; D017705:Lignans; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione