The polymorphism rs2480258 within CYP2E1 is associated with different rates of acrylamide metabolism in vivo in humans

Pellé, Lucia; Carlsson, Henrik; Cipollini, Monica; Bonotti, Alessandra; Foddis, Rudy; Cristaudo, Alfonso; Romei, Cristina; Elisei, Rossella; Gemignani, Federica; Törnqvist, Margareta; Landi, Stefano

doi:10.1007/s00204-018-2211-2

Cited by 9 publications

(3 citation statements)

References 19 publications

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“…A strong correlation between AA and its metabolite GA was expected as it has been observed earlier, despite individual variation in the ratio of adduct levels, 65 primarily due to polymorphism of the metabolic enzyme CYP2E1. 66 The comparison of adduct levels from the electrophiles in Figure 7 in the blood samples from schoolchildren thus gave no clear indication concerning the origin of the HPA-Val adduct.…”

Section: Resultsmentioning

confidence: 97%

Pathways to Identify Electrophiles In Vivo Using Hemoglobin Adducts: Hydroxypropanoic Acid Valine Adduct and Its Possible Precursors

Vryonidis

Karlsson

Aasa

et al. 2022

Chem. Res. Toxicol.

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Analytical methods and tools for the characterization of the human exposome by untargeted mass spectrometry approaches are advancing rapidly. Adductomics methods have been developed for untargeted screening of short-lived electrophiles, in the form of adducts to proteins or DNA, in vivo. The identification of an adduct and its precursor electrophile in the blood is more complex than that of stable chemicals. The present work aims to illustrate procedures for the identification of an adduct to N-terminal valine in hemoglobin detected with adductomics, and pathways for the tracing of its precursor and possible exposure sources. Identification of the adduct proceeded via preparation and characterization of standards of adduct analytes. Possible precursor(s) and exposure sources were investigated by measurements in blood of adduct formation by precursors in vitro and adduct levels in vivo. The adduct was identified as hydroxypropanoic acid valine (HPA-Val) by verification with a synthesized reference. The HPA-Val was measured together with other adducts (from acrylamide, glycidamide, glycidol, and acrylic acid) in human blood (n = 51, schoolchildren). The HPA-Val levels ranged between 6 and 76 pmol/g hemoglobin. The analysis of reference samples from humans and rodents showed that the HPA-Val adduct was observed in all studied samples. No correlation of the HPA-Val level with the other studied adducts was observed in humans, nor was an increase in tobacco smokers observed. A small increase was observed in rodents exposed to glycidol. The formation of the HPA-Val adduct upon incubation of blood with glycidic acid (an epoxide) was shown. The relatively high adduct levels observed in vivo in relation to the measured reactivity of the epoxide, and the fact that the epoxide is not described as naturally occurring, suggest that glycidic acid is not the only precursor of the HPA-Val adduct identified in vivo. Another endogenous electrophile is suspected to contribute to the in vivo HPA-Val adduct level.

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Section: Resultsmentioning

confidence: 97%

Pathways to Identify Electrophiles In Vivo Using Hemoglobin Adducts: Hydroxypropanoic Acid Valine Adduct and Its Possible Precursors

Vryonidis

Karlsson

Aasa

et al. 2022

Chem. Res. Toxicol.

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“…10 In a separate study, they observed a decreased glycidamide to acrylamide ratio in homozygous carriers of the T allele. 16 Duale et al did not observe differences in the ratio of glycidamide to acrylamide for 2 SNPs in CYP2E1 (rs6413419 and rs2515641); rs6413419 is a missense mutation. In addition, they did not observe a difference in the ratio of glycidamide to acrylamide for rs1051740 in EPHX1, similar to our study.…”

Section: Discussionmentioning

confidence: 95%

Cord blood acrylamide levels and birth size, and interactions with genetic variants in acrylamide-metabolizing genes

Hogervorst

Vesper²,

Madhloum

et al. 2019

Preprint

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Background Up to now, 3 epidemiological studies have shown clear inverse associations between prenatal acrylamide exposure and birth size. In addition to studying the association between acrylamide and birth size, we investigated the interaction between acrylamide and polymorphisms in acrylamide-metabolising genes, with the aim of probing the causality of the inverse relationship between acrylamide and fetal growth. Methods We investigated the association between prenatal acrylamide exposure (acrylamide and glycidamide to hemoglobin adduct levels (AA-Hb and GA-Hb) in cord blood) and birth weight, length and head circumference in 443 newborns of the ENVIRONAGE (ENVIRonmental influence ON AGEing in early life) birth cohort. In addition, we studied interaction with single nucleotide polymorphism (SNPs) in CYP2E1, EPHX1 and GSTP1, using multiple linear regression analysis. Results Compared to neonates in the lowest quartile of AA-Hb in cord blood, the body weight, length and head circumference of neonates in the highest quartile were -101 grams (95% CI: -208, 7; p for trend = 0.12), -0.13 centimetres (95% CI: -0.62, 0.36; p for trend = 0.69) and -0.41 centimetres (-0.80, -0.01; p for trend = 0.06) lower, respectively. For GA-Hb, the corresponding effect estimates were -222 grams (95% CI: -337, -108; p for trend = 0.001), -0.85 (95% CI: -1.38, -0.33; p for trend = 0.02) and -0.55 (95% CI: -0.98, -0.11; p for trend = 0.01), respectively. The associations for GA-Hb were similar or stronger in newborns of non-smoking mothers. There was no statistically significant interaction between acrylamide exposure and the studied genetic variations but there was a trend of stronger inverse associations with birth weight and head circumference among newborns with homozygous wildtypes alleles for the CYP2E1 SNPS and with variant alleles for a GSTP1 SNP (rs1138272). Conclusions Prenatal dietary acrylamide exposure, specifically in the form of its metabolite glycidamide, was inversely associated with birth weight, length and head circumference. The interaction pattern with SNPs in CYP2E1, although not statistically significant, is an indication for the causality of this association. Other studies are needed to corroborate this finding.

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“…In addition, the T-allele of rs2480258 was found to reduce CYP2E1 activity and thus decrease its ability to convert AA into GA in the body. 17 Therefore, the ratio of AA and GA are varying. Previously, there have been studies that analyze AA in DBS sample of lung cancer patients, though that study only analyzes AA without GA. 7 The result of said study 7 shows that there is no significant difference between AA levels of lung cancer patients and healthy subjects.…”

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confidence: 99%

Analysis of Acrylamide and Glycidamide in Dried Blood Spot of Smokers Using Ultra-High-Performance Liquid Chromatography–Tandem Mass Spectrometry

Harahap

Lahilla

Jautan

et al. 2022

DDDT

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Introduction:Acrylamide is a genotoxic substance that can be found in cigarette smoke. Acrylamide is metabolized by the CYP2E1 enzyme in the body to form glycidamides, an epoxide that is reactive to DNA and can form carcinogenic adducts. Therefore, exposure to acrylamide can potentially cause cancer. This study aims to analyze the levels of acrylamide and glycidamide in dried blood spot samples of smokers using propanamide as an internal standard and non-smokers as the control subjects. Methods: Dried blood spot samples were extracted using the protein precipitation method and then analyzed by liquid chromatography-tandem mass spectrometry. Mass detection was performed using positive type electro spray ionization and multiple reaction monitoring type with m/z 72.0>55.02 for acrylamide, 88.1>45.0 for glycidamide, and 74.0>57.1 for propanamide as the internal standard. Results: Acrylamide and glycidamide levels in the dried blood spot sample of smokers ranged between 3.91 -10.25 µg/mL and 1.006-3.58 µg/mL, respectively. Data of the non-smokers on acrylamide and glycidamide levels were 0.75-3.16 µg/mL and 0-0.91 µg/mL. Discussion: The significant value of acrylamide and glycidamide between smokers and non-smokers was p < 0.05, which showed that there is a significant difference between acrylamide and glycidamide concentration in smokers and non-smoker subjects. The results of this study suggest that dried blood spots can be used to determine acrylamide and glycidamide levels in humans. Theoretically, acrylamide and glycidamide concentration should correlate to each other; however in reality, there are other factors (such as CYP2E1 polymorphism, dietary intake, etc) that can cause variation in their respective concentration.

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The polymorphism rs2480258 within CYP2E1 is associated with different rates of acrylamide metabolism in vivo in humans

Cited by 9 publications

References 19 publications

Pathways to Identify Electrophiles In Vivo Using Hemoglobin Adducts: Hydroxypropanoic Acid Valine Adduct and Its Possible Precursors

Pathways to Identify Electrophiles In Vivo Using Hemoglobin Adducts: Hydroxypropanoic Acid Valine Adduct and Its Possible Precursors

Cord blood acrylamide levels and birth size, and interactions with genetic variants in acrylamide-metabolizing genes

Analysis of Acrylamide and Glycidamide in Dried Blood Spot of Smokers Using Ultra-High-Performance Liquid Chromatography–Tandem Mass Spectrometry

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