Toxicokinetics of acrylamide in rats and humans following single oral administration of low doses.
The rodent carcinogen acrylamide (AA) is formed during preparation of starch-containing foods. AA is partly metabolized to the genotoxic epoxide glycidamide (GA). After metabolic processing, the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), rac-N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) and rac-N-acetyl-S-(1-carbamoyl-moyl-2-hydroxyethyl)-L-cysteine (iso-GAMA) are excreted with urine. In humans, AAMA can be sulfoxidized to AAMA-sulfoxide. The aim of this study was to assess potential species-differences in AA-toxicokinetics in rats and humans after single oral administration of doses similar to the daily human dietary exposure. Male Fischer 344 rats (n=5/dose group) were administered 20 and 100 microg/kg b.w. (13)C(3)-AA in deionized water via oral gavage. Human subjects (n=3/gender) were orally administered 0.5 and 20 microg/kg b.w. (13)C(3)-AA with drinking water. Urine samples were collected in intervals for 96 and 94 h, respectively. Urinary concentrations of (13)C(3)-AAMA, (13)C(3)-GAMA and (13)C(3)-AAMA-sulfoxide were monitored by liquid chromatography-tandem mass spectrometry. The recovered urinary metabolites accounted for 66.3% and 70.5% of the 20 and 100 microg/kg b.w. doses in rats and for 71.3% and 70.0% of the 0.5 and 20 microg/kg b.w. doses in humans. In rats, (13)C(3)-AAMA accounted for 33.6% and 38.8% of dose and 32.7% and 31.7% of dose was recovered as (13)C(3)-GAMA; (13)C(3)-AAMA-sulfoxide was not detected in rat urine. In humans, (13)C(3)-AAMA, (13)C(3)-GAMA and (13)C(3)-AAMA-sulfoxide accounted for 51.7% and 49.2%, 6.3% and 6.4% and 13.2% and 14.5% of the applied dose, respectively. The obtained results suggest that the extent of AA bioactivation to GA in humans is lower than in rodents.
Kopp
Eva Katharina
EK
Department of Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
Dekant
Wolfgang
W
D020106:Acrylamide / Q000493:pharmacokinetics* / Q000633:toxicity*; D000284:Administration, Oral; D000328:Adult; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D004032:Diet; D005260:Female; D006801:Humans; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D021241:Spectrometry, Mass, Electrospray Ionization; D055815:Young Adult
D020106:Acrylamide