In vivo role of cytochrome P450 2E1 and glutathione-S-transferase activity for acrylamide toxicokinetics in humans.
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>G and 341T>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.
Doroshyenko
Oxana
O
Department of Pharmacology, University of Cologne, Cologne, Germany.
Fuhr
Uwe
U
Kunz
Daria
D
Frank
Dorothee
D
Kinzig
Martina
M
Jetter
Alexander
A
Reith
Yvonne
Y
Lazar
Andreas
A
Taubert
Dirk
D
Kirchheiner
Julia
J
Baum
Matthias
M
Eisenbrand
Gerhard
G
Berger
Franz-Ingo
FI
Bertow
Daniel
D
Berkessel
Albrecht
A
Sörgel
Fritz
F
Schömig
Edgar
E
Tomalik-Scharte
Dorota
D
D020106:Acrylamide / Q000493:pharmacokinetics* / Q000633:toxicity; D002273:Carcinogens / Q000493:pharmacokinetics*; D002753:Chlorzoxazone / Q000008:administration & dosage; D018592:Cross-Over Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004221:Disulfiram / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D000431:Ethanol / Q000008:administration & dosage; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D002273:Carcinogens; D004791:Enzyme Inhibitors; D020106:Acrylamide; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; D002753:Chlorzoxazone; D004221:Disulfiram