Biomarkers of exposure to heterocyclic amines: approaches to improve the exposure assessment

Alexander, Jan; Reistad, R.; Hegstad, Solfrid; Frandsen, Henrik Lauritz; Ingebrigtsen, Kristian; Paulsen, Jan Erik; Becher, Georg

doi:10.1016/s0278-6915(02)00053-4

Cited by 60 publications

(72 citation statements)

References 47 publications

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“…5-OH-PhIP and PhIP-5-sulfate are surrogate markers for the levels of the ultimate genotoxic nitrenium radical cation that forms DNA adducts (Supplemental Fig. 1) (Alexander et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

Bcrp1;Mdr1a/b;Mrp2 Combination Knockout Mice: Altered Disposition of the Dietary Carcinogen PhIP (2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine) and Its Genotoxic Metabolites

et al. 2013

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The multidrug transporters breast cancer resistance protein (BCRP), multidrug-resistance protein 1 (MDR1), and multidrugresistance-associated protein (MRP) 2 and 3 eliminate toxic compounds from tissues and the body and affect the pharmacokinetics of many drugs and other potentially toxic compounds. The food-derived carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine) is transported by BCRP, MDR1, and MRP2. To investigate the overlapping functions of Bcrp1, Mdr1a/b, and Mrp2 in vivo, we generated Bcrp1;Mdr1a/b;Mrp2 2/2 mice, which are viable and fertile. These mice, together with Bcrp1;Mrp2;Mrp3 2/2 mice, were used to study the effects of the multidrug transporters on the pharmacokinetics of PhIP and its metabolites. Thirty minutes after oral or intravenous administration of PhIP (1 mg/kg), the PhIP levels in the small intestine were reduced 4-to 6-fold in Bcrp1;Mdr1a/b;Mrp2 2/ 2 and Bcrp1;Mrp2;Mrp3 2/2 mice compared with wild-type mice. Fecal excretion of PhIP was reduced 8-to 20-fold in knockouts. Biliary PhIP excretion was reduced 41-fold in Bcrp1;Mdr1a/b;Mrp2 2/2 mice. Biliary and small intestine levels of PhIP metabolites were reduced in Bcrp1;Mrp2-deficient mice. Furthermore, in both knockout strains, kidney levels and urinary excretion of genotoxic PhIPmetabolites were significantly increased, suggesting that reduced biliary excretion of PhIP and PhIP metabolites leads to increased urinary excretion of these metabolites and increased systemic exposure. Bcrp1 and Mdr1a limited PhIP brain accumulation. In Bcrp1;Mrp2;Mrp3 2/2 , but not Bcrp1; Mdr1a/b;Mrp 2/2 mice, the carcinogenic metabolites N2-OHPhIP (2-hydroxyamino-1-methyl-6-phenylimidazo [4,5-b]pyridine) and PhIP-5-sulfate (a genotoxicity marker) accumulated in liver tissue, indicating that Mrp3 is involved in the sinusoidal secretion of these compounds. We conclude that Bcrp1, Mdr1a/b, Mrp2, and Mrp3 significantly affect tissue disposition and biliary and fecal elimination of PhIP and its carcinogenic metabolites and may affect PhIP-induced carcinogenesis as a result.

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“…5-OH-PhIP and PhIP-5-sulfate are surrogate markers for the levels of the ultimate genotoxic nitrenium radical cation that forms DNA adducts (Supplemental Fig. 1) (Alexander et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

Bcrp1;Mdr1a/b;Mrp2 Combination Knockout Mice: Altered Disposition of the Dietary Carcinogen PhIP (2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine) and Its Genotoxic Metabolites

et al. 2013

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“…We were not able to include pictures of different level of doneness in this cohort, which according to a recent study, may have improved our estimates (52). Several studies have examined hair, DNA adducts, protein adducts as potential biomarkers for long-term HCA intake; but a long-term biomarker has yet to be established (53–57). Therefore, to overcome the various issues of measurement error, it is crucial to develop good long-term biomarkers of HCAs.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in Xenobiotic Metabolizing Genes, Intakes of Heterocyclic Amines and Red Meat, and Postmenopausal Breast Cancer

Lee

Cox

et al. 2013

Nutrition and Cancer

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Heterocyclic amines (HCAs) are mutagenic compounds generated when meats are cooked at high temperature and for long duration. The findings from previous studies on the relation between HCAs and breast cancer are inconsistent, possibly due to genetic variations in the enzymes metabolizing HCAs. To evaluate whether the associations of intakes of estimated HCAs, meat-derived mutagenicity (MDM), and red meat with risk of postmenopausal breast cancer were modified by N-acetyltransferase 2 (NAT2) acetylator genotype or cytochrome P450 1A2 -164 A/C (CYP1A2) polymorphism, we conducted a nested case-control study with 579 cases and 981 controls within a prospective cohort, the Nurses’ Health Study (NHS). HCAs and MDM intakes were derived using a cooking method questionnaire administered in 1996. NAT2 acetylator genotype, the CYP1A2 polymorphism, and intakes of HCAs, MDM, and red meat were not associated with risk of postmenopausal breast cancer. There was also no interaction between NAT2 acetylator genotype or CYP1A2 polymorphism and HCAs and MDM and red meat intake in relation to breast cancer. These results do not support the hypothesis that genetic polymorphisms of xenobiotic enzymes involved in the metabolism of HCAs may modify the associations between intakes of red meat or meat-related mutagens and breast cancer risk.

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“…There are several problems associated with the estimation of the intake of HCAs by means of dietary assessments, for example difficulties in getting accurate dietary information [10,11], and lacking data on HCA concentrations in representative food samples [12]. HCAs are absorbed and metabolized by humans, and have a half-life of less than 12 h [13].…”

Section: Pyridine;mentioning

confidence: 99%

Hollow fibre‐supported liquid membrane extraction and LC‐MS/MS detection for the analysis of heterocyclic amines in urine samples

Busquets¹,

Jönsson²,

Frandsen³

et al. 2009

Molecular Nutrition Food Res

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Heterocyclic amines (HCAs) are potent mutagens/carcinogens to which humans are frequently exposed through the consumption of cooked meat and fish food. The effect of normal intake of HCAs and their role in the aetiology of human cancer is unknown. To some extent, limitations of the existing analytical methods in monitoring the low levels of HCAs in biological samples have hindered obtaining conclusive results. In this study, a method for the analysis of HCAs in human urine has been studied to detect HCAs and metabolites at levels resulting from consumption of food cooked at ordinary conditions. The analytical method consisted of extraction and clean-up by the novel technique liquid-phase microextraction combined with LC-MS/MS. The effect of pH during the extraction and hydrolysis step was examined. High sensitivity was achieved when the extraction was performed in raw urine adjusted to pH 5.5, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine being detected from 2 pg/g urine, levels comparable with a normal exposure. Good reproducibility and repeatability was obtained for 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, below 9% using isotopic dilution. The performance of the method on 9H-pyrido[3,4-b]indole, 2-amino-1-methyl-6-(4'-hydroxyphenyl)imidazo[4,5-b]pyridine and 2-amino-1-methyl-6-(5-hydroxy)phenylimidazo[4,5-b]pyridine was also studied.

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Biomarkers of exposure to heterocyclic amines: approaches to improve the exposure assessment

Cited by 60 publications

References 47 publications

Bcrp1;Mdr1a/b;Mrp2 Combination Knockout Mice: Altered Disposition of the Dietary Carcinogen PhIP (2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine) and Its Genotoxic Metabolites

Bcrp1;Mdr1a/b;Mrp2 Combination Knockout Mice: Altered Disposition of the Dietary Carcinogen PhIP (2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine) and Its Genotoxic Metabolites

Polymorphisms in Xenobiotic Metabolizing Genes, Intakes of Heterocyclic Amines and Red Meat, and Postmenopausal Breast Cancer

Hollow fibre‐supported liquid membrane extraction and LC‐MS/MS detection for the analysis of heterocyclic amines in urine samples

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