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ToxSci Advance Access published online on January 8, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfn269
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Biomarkers of human exposure to acrylamide and relation to polymorphisms in metabolizing genes

Nur Duale*, Thomas Bjellaas*, Jan Alexander*, Georg Becher*, Margaretha Haugen*, Jan Erik Paulsen*, Henrik Frandsen{dagger}, Pelle Thonning Olesen{dagger} and Gunnar Brunborg*,1

* Norwegian Institute of Public Health, Division of Environmental Medicine, P.O. Box 4404, Nydalen, NO-0403 Oslo, Norway {dagger} National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark

1 Corresponding author Gunnar Brunborg, Email: gunnar.brunborg{at}fhi.no, Norwegian Institute of Public Health, Division of Environmental Medicine, P.O. Box 4404, Nydalen, NO-0403 Oslo, Norway, Phone: + 47 2107 6426, FAX: + 47 2107 6686

Received September 18, 2008; revision received November 26, 2008; accepted December 23, 2008


  Abstract

Acrylamide (AA) is formed in heat treated carbohydrate rich foods in the so-called Maillard reaction. AA is readily abosorbed in the body and converted to glycidamide (GA) by epoxidation by the CYP2E1 enzyme. Both AA and GA may be detoxified through direct conjunction to glutathione by glutathione-transferases and GA by hydrolysis to glyceramide. Recently, we reported that biomarkers of AA exposure reflect intake of major food sources of AA; there were large inter-individual variations in the blood ratio of GA-Hb/AA-Hb (GA- and AA- hemoglobin adducts).

In this study we investigated whether the ratio of GA-Hb/AA-Hb in subjects could be related to polymorphic differences in genes coding for metabolizing enzymes CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1, all being expected to be involved in the activation and detoxification of AA-associated adducts. We found significant associations between GSTM1 and GSTT1 genotypes and the ratio of GA-Hb/AA-Hb (p=0.039 and p=0.006, respectively). The ratio of GA-Hb/AA-Hb in individuals with the combined GSTM1- and GSTT1-null variants were significantly (p=0.029) higher than those with the wild-type genotypes. Although the number of subjects was small, there were also significant associations with other combinations; CYP2E1 (Val179Val) plus GSTM1-null (p=0.022); CYP2E1 (Val/Val), GSTM1-null plus GSTT1-null (p=0.047); and CYP2E1 (Val/Val), GSTT1 null, EPHX1 (Tyr113Tyr) plus EPHX1 (His139Arg) (p=0.018). Individuals with these combined genotypes had significantly higher blood ratio of GA-Hb/AA-Hb than other combinations.

The observed associations correspond with what would be expected from the relative roles of these enzymes in activation and detoxification of AA, except for individuals with the EPHX1 (His139Arg) variant. The internal dose of genotoxic metabolite and also the concentration of AA in blood seem to be affected by these polymorphic genes. The genotypes and their combination may constitute useful biomarkers for the assessment of individual susceptibility to AA intake, and could add to the precision of epidemiological studies of dietary cancer.

Key Words: cytochrome P450 2E1; glutathione-transferase; SNPs and polymorphisms; glycidamide; acrylamide; biotransformation < Biotransformation and Toxicokinetics.


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