Absence of acrylamide-induced genotoxicity in CYP2E1-null mice: Evidence consistent with a glycidamide-mediated effect

247

186

Background: Acrylamide, a probable human carcinogen, was detected in various heat-treated carbohydrate-rich foods in 2002. The few epidemiologic studies done thus far have not shown a relationship with cancer. Our aim was to investigate the association between acrylamide intake and endometrial, ovarian, and breast cancer risk. Methods: The Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55-69 years. At baseline (1986), a random subcohort of 2,589 women was selected using a case cohort analysis approach for analysis. The acrylamide intake of subcohort members and cases was assessed with a food frequency questionnaire and was based on chemical analysis of all relevant Dutch foods. Subgroup analyses were done for never-smokers to eliminate the influence of smoking; an important source of acrylamide. Results: After 11.3 years of follow-up, 327, 300, and 1,835 cases of endometrial, ovarian, and breast cancer,

Section: Discussionmentioning

confidence: 99%

“…These variables are diabetes (ever/never diagnosis of diabetes), obesity (BMI > 30 kg/m 2 ), smoking (both duration of smoking in years and number of cigarettes smoked per day), alcohol consumption (0, >0-5, >5 g/day), and physical activity (<30, 30 to <60, 60 to <90, z90 minutes/day; refs. [35][36][37][38].…”

Section: Methodsmentioning

confidence: 99%

A Prospective Study of Dietary Acrylamide Intake and the Risk of Endometrial, Ovarian, and Breast Cancer

Hogervorst

Schouten

Konings

et al. 2007

247

186

“…Humans are exposed to relatively high doses of acrylamide because this compound is formed in food during cooking (16,17). Acrylamide can be converted to the epoxide glycidamide by cytochrome P450 2E1 (18). Both compounds are electrophilically reactive.…”

Section: Introductionmentioning

confidence: 99%

Global Gene Expression Analysis in Cord Blood Reveals Gender-Specific Differences in Response to Carcinogenic Exposure In Utero

Hochstenbach

Leeuwen

Gmuender

et al. 2012

Background: It has been suggested that fetal carcinogenic exposure might lead to predisposition to develop cancer during childhood or in later life possibly through modulation of the fetal transcriptome. Because gender effects in the incidence of childhood cancers have been described, we hypothesized differences at the transcriptomic level in cord blood between male and female newborns as a consequence of fetal carcinogenic exposure. The objective was to investigate whether transcriptomic responses to dietary genotoxic and nongenotoxic carcinogens show gender-specific mechanisms-of-action relevant for chemical carcinogenesis.Methods: Global gene expression was applied in umbilical cord blood samples, the CALUX-assay was used for measuring dioxin(-like), androgen(-like), and estrogen(-like) internal exposure, and acrylamide-hemoglobin adduct levels were determined by mass spectrometry adduct-FIRE-procedure TM . To link gene

“…In humans, the urinary concentration ratio of AAMA and GAMA, which is considered as a metric to describe the extent of conversion of acrylamide to glycidamide (9) and thus reflects internal exposure, varies considerably between subjects (22,23). It is unclear to which extent the activity and expression of metabolizing enzymes influences acrylamide metabolism and, therefore, contributes to differences in acrylamide disposition and carcinogenicity among species and between individuals (20,33). The objectives of the present study were to clarify the role of CYP2E1 and GSTs and their genetic variants for the in vivo metabolism of acrylamide in humans and, thus, to improve the cancer risk assessment for humans through acrylamide intake with food.…”

Section: Introductionmentioning

confidence: 99%

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

Doroshyenko

Fuhr

Kunz

et al. 2009

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 selfprepared 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. (Cancer Epidemiol