The role of different cytochrome P450 isoforms in in vitro chloroform metabolism

Journal of Biochemical Toxicology
E TestaiL Vittozzi

Abstract

The two CHCl3 activation pathways have been studied in incubations at different oxygenation conditions with hepatic microsomes from control Sprague Dawley (SD) rats or SD rats treated with different cytochrome P450 inducers (acetone, phenobarbital, pyrazole, dexamethasone, and beta-naphthoflavone). The present results provide direct evidence that CHCl3 concentration is critical in determining the role of different cytochrome P450 isoforms (CYP) and the related effects of metabolic inducers. At 0.1 mM CHCl3 concentration, the only major contribution to its oxidative biotransformation in liver microsomes from untreated rats was due to CYP2E1, as shown by metabolic inhibition due to 4-methylpyrazole or by anti-CYP2E1 antibodies. Moreover, animal treatments with acetone and pyrazole increased the production of adducts of phosgene to microsomal phospholipid by about 10-15 times. At 5 mM chloroform, in control rat liver microsomes, CYP2B1/2 was the major participant responsible for chloroform activation, while CYP2E1 and CYP2C11 were also significantly involved. Consistently, at this chloroform concentration, the effect of phenobarbital (CYP2B1/2 inducer) was maximal, producing very high levels of adducts. The reductive pathway was e...Continue Reading

Citations

Aug 31, 2011·Archives of Environmental Contamination and Toxicology·Armando Vega-LópezEthel A García-Latorre
Jul 1, 2002·Environmental Toxicology and Pharmacology·Franca M BurattiEmanuela Testai
May 8, 2004·Journal of Toxicology and Environmental Health. Part a·John C LipscombJohn Laskey
Apr 1, 2005·Journal of Toxicology and Environmental Health. Part a·Annie St-PierreRobert Tardif
Nov 13, 2003·Journal of Toxicology and Environmental Health. Part a·Annie St-PierreRobert Tardif
Nov 13, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Alan F SassoJohn C Lipscomb
Mar 22, 2014·Environmental Health Perspectives·Anne M RiedererKyle Steenland
Aug 2, 2015·Current Environmental Health Reports·Cristina M VillanuevaPatrick Levallois
Feb 14, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Simonetta GemmaEmanuela Testai

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