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Doroshyenko, Oxana; Fuhr, Uwe; Kunz, Daria; Frank, Dorothee; Kinzig, Martina; Jetter, Alexander; Reith, Yvonne; Lazar, Andreas; Taubert, Dirk; Kirchheiner, Julia; Baum, Matthias; Eisenbrand, Gerhard; Berger, Franz-Ingo; Bertow, Daniel; Berkessel, Albrecht; Sörgel, Fritz; Schömig, Edgar; Tomalik-Scharte, Dorota

In vivo Role of Cytochrome P450 2E1 and Glutathione-S-Transferase Activity for Acrylamide Toxicokinetics in Humans

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  • Media type: E-Article
  • Title: In vivo Role of Cytochrome P450 2E1 and Glutathione-S-Transferase Activity for Acrylamide Toxicokinetics in Humans
  • Contributor: Doroshyenko, Oxana; Fuhr, Uwe; Kunz, Daria; Frank, Dorothee; Kinzig, Martina; Jetter, Alexander; Reith, Yvonne; Lazar, Andreas; Taubert, Dirk; Kirchheiner, Julia; Baum, Matthias; Eisenbrand, Gerhard; Berger, Franz-Ingo; Bertow, Daniel; Berkessel, Albrecht; Sörgel, Fritz; Schömig, Edgar; Tomalik-Scharte, Dorota
  • imprint: American Association for Cancer Research (AACR), 2009
  • Published in: Cancer Epidemiology, Biomarkers & Prevention
  • Language: English
  • DOI: 10.1158/1055-9965.epi-08-0832
  • ISSN: 1055-9965; 1538-7755
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:p>Acrylamide, a potential food carcinogen in humans, is biotransformed to the epoxide glycidamide in vivo. Both acrylamide and glycidamide are conjugated with glutathione, possibly via glutathione-S-transferases (GST), and bind covalently to proteins and nucleic acids. We investigated acrylamide toxicokinetics in 16 healthy volunteers in a four-period change-over trial and evaluated the respective role of cytochrome P450 2E1 (CYP2E1) and GSTs. Participants ingested self-prepared potato chips containing acrylamide (1 mg) without comedication, after CYP2E1 inhibition (500 mg disulfiram, single dose) or induction (48 g/d ethanol for 1 week), and were phenotyped for CYP2E1 with chlorzoxazone (250 mg, single dose). Unchanged acrylamide and the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) and N-acetyl-S-(2-hydroxy-2-carbamoylethyl)-cysteine (GAMA) accounted for urinary excretion [geometric mean (percent coefficient of variation)] of 2.9% (42), 65% (23), and 1.7% (65) of the acrylamide dose in the reference period. Hemoglobin adducts increased clearly following the acrylamide test-meal. The cumulative amounts of acrylamide, AAMA, and GAMA excreted and increases in AA adducts changed significantly during CYP2E1 blockade [point estimate (90% confidence interval)] to the 1.34-fold (1.14-1.58), 1.18-fold (1.02-1.36), 0.44-fold (0.31-0.61), and 1.08-fold (1.02-1.15) of the reference period, respectively, but were not changed significantly during moderate CYP2E1 induction. Individual baseline CYP2E1 activity, CYP2E1*6, GSTP1 313A&amp;gt;G and 341T&amp;gt;C single nucleotide polymorphisms, and GSTM1-and GSTT1-null genotypes had no major effect on acrylamide disposition. The changes in acrylamide toxicokinetics upon CYP2E1 blockade provide evidence that CYP2E1 is a major but not the only enzyme mediating acrylamide epoxidation in vivo to glycidamide in humans. No obvious genetic risks or protective factors in xenobiotic-metabolizing enzymes could be determined for exposed subjects. (Cancer Epidemiol Biomarkers Prev 2009;18(2):433–43)</jats:p>
  • Access State: Open Access