PhIP metabolites in human urine after consumption of well-cooked chicken

Kulp, Kristen S.; Knize, Mark G.; Fowler, Nicola; Salmon, Cynthia P.; Felton, James S.

doi:10.1016/j.jchromb.2003.09.032

Cited by 42 publications

(63 citation statements)

References 62 publications

(71 reference statements)

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“…8,10,11,19,39,40 Large interindividual differences in the rates of PhIP N-oxidation producing the carcinogenic intermediate N-OH-PhIP have previously been observed. 30,41 However, we report here for the first time that its hepatic glucuronidation is also highly variable. The current research led to important additional findings on the influence of specific genetic polymorphisms in the UGT-mediated hepatic detoxification pathway potentially influencing the exposure to HCAs and subsequent cancer risk.…”

Section: Discussionmentioning

confidence: 65%

“…N-OH-PhIP glucuronide metabolites were initially identified in a pool of 8 human liver microsomes based on HPLC co-elution with authentic metabolite standards, mass spectral analysis, and susceptibility to enzymatic cleavage. Chromatographic separation of liver incubation reactions indicated four metabolite peaks eluting at 1.91 (peak 1), 3.55 (peak 2), 3.92 (peak 3), and 4.86 (peak 4) minutes ( An additional glucuronide N-OH-PhIP-G 2 (Glucu 2) corresponding to peak 2 that has never been previously described demonstrated a fragmentation profile similar to N-OH-PhIP-N 2 G. To determine whether variability in N-OH-PhIP glucuronidation observed in vivo 14,30 can be observed at the hepatic level, enzymatic assays were performed with microsomes prepared from 48 liver specimens. The formation of N-OH-PhIP-N 2 G was predominant in all tested livers, representing 40% to 93% of total glucuronides (28-fold variation; 23 to 651 pmol/ min/mg).…”

Section: N-oh-phip Glucuronidation Profiles and Variability In Human mentioning

confidence: 99%

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UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver

et al. 2005

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PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-f]pyridine), the most abundant heterocyclic amine in diet, is involved in the etiology of cancer. PhIP and its carcinogenic metabolite Nhydroxy-PhIP (N-OH-PhIP) are extensively conjugated by UDP-glucuronosyltransferase (UGTs) with wide variability. This study aimed to determine the genetic influence of UGTs on the hepatic detoxification of this carcinogen. The formation of N-OH-PhIP glucuronides was studied in 48 human liver samples by mass spectrometry. Liver samples were genotyped for common polymorphisms and correlated with UGT protein levels and N-OH-PhIP glucuronidation activities. The formation of four different N-OH-PhIP glucuronide metabolites was observed in all livers. The major metabolite was N-OH-PhIP-N 2 -glucuronide (N 2 G), which is the primary metabolite found in human urine, and showed a high interindividual variability (up to 28-fold). Using an heterologous expression system, the bilirubin-conjugating UGT1A1 enzyme was identified among all known UGTs (n ‫؍‬ 16) as the predominant enzyme involved. The significant correlation between UGT1A1 protein content and formation of N 2 G (Rs ‫؍‬ 0.87; P < .0001) suggests a critical role for UGT1A1 in the hepatic metabolism of this carcinogen. UGT1A1 expression was strongly determined by the presence of the common promoter polymorphisms, UGT1A1*28 (TATA box polymorphism) (P ‫؍‬ .0031), ؊3156G/A (P ‫؍‬ .0006) and ؊3279G/T (P ‫؍‬ .0017), and rates of N 2 G were indeed correlated with these polymorphisms (P < .05), whether analyzed individually or in combination (haplotypes). In conclusion,

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Section: Discussionmentioning

confidence: 65%

Section: N-oh-phip Glucuronidation Profiles and Variability In Human mentioning

confidence: 99%

UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver

et al. 2005

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“…In the case of MeIQx, the 8-carboxylic acid derivative, which is formed by CYP1A2 [60], accounts for more than 50% of the metabolites of MeIQx in human urine [42]. Moreover, a higher percent of the dose of MeIQx and PhIP also appears to be converted into N-hydroxylated metabolites in humans than rodents in vivo, based upon the detection of the N-glucuronide conjugates of the N-hydroxy-HAA metabolites in urine [24,42,45,46]. The superior catalytic efficiency of human CYP1A2 over rat CYP1A2 in…”

Section: Species Differences In Regioselectivity Of Cyp1a2-catalyzed mentioning

confidence: 99%

“…Human SULT1A1 appears to be the principal isoform involved in this conjugation pathway [43]. The sulfamation of PhIP is also catalyzed by rat liver cytosols [120]; however, this pathway has not been reported in vivo in rodents or humans [24,26,45,46].…”

Section: Sulfotransferases and Polymorphisms Affecting Haa Metabolismmentioning

confidence: 99%

Interspecies metabolism of heterocyclic aromatic amines and the uncertainties in extrapolation of animal toxicity data for human risk assessment

Turesky¹

2005

Mol. Nutr. Food Res.

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Heterocyclic aromatic amines (HAAs) are potent bacterial mutagens that are formed in cooked meats, tobacco smokes condensate, and diesel exhaust. Many HAAs are carcinogenic in experimental animal models. Because of their wide-spread occurrence in the diet and environment, HAAs may contribute to some common types of human cancers. The extrapolation of animal toxicity data on HAAs to asses human health risk has many uncertainties, which can lead to tenuous risk assessment estimates. Perhaps the most critical and variable parameters in interspecies extrapolation are the effects of dose, species differences in catalytic activities of xenobiotic metabolism enzymes (XMEs), human XME polymorphisms that lead to interindividual differences in carcinogen metabolism and dietary constituents that may either augment or diminish the carcinogenic potency of these genotoxins. The impact of these parameters on the metabolism and toxicological properties of HAAS and uncertainties in extrapolation of animal toxicity data for human risk assessment are presented in this article.

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“…On the other hand, the involvement of the intestinal microbiota in the digestive fate of heterocyclic amines remains poorly investigated (27). Recent research showed that PhIP metabolites excreted in 0-to 24-h urine represented 17% Ϯ 10% of the ingested PhIP in a meat matrix (28). In an earlier study with patients administered PhIP in capsules, 90% of the ingested dose was recovered in the urine (29), indicating that PhIP provided in capsule form is more bioavailable than that via meat ingestion.…”

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confidence: 99%

Isolation and Characterization of Human Intestinal Bacteria Capable of Transforming the Dietary Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5- b ]Pyridine

Vanhaecke

Vercruysse

Boon

et al. 2008

Appl Environ Microbiol

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2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a carcinogenic heterocyclic aromatic amine formed in meat products during cooking. Although the formation of hazardous PhIP metabolites by mammalian enzymes has been extensively reported, research on the putative involvement of the human intestinal microbiota in PhIP metabolism remains scarce. In this study, the in vitro conversion of PhIP into its microbial derivate, 7-hydroxy-5-methyl-3-phenyl-6,7,8,9-tetrahydropyrido[3,2:4,5]imidazo[1,2-a]pyrimidin-5-ium chloride (PhIP-M1), by fecal samples from 18 human volunteers was investigated. High-performance liquid chromatography analysis showed that all human fecal samples transformed PhIP but with efficiencies ranging from 1.8 to 96% after 72 h of incubation. Two PhIP-transforming strains, PhIP-M1-a and PhIP-M1-b, were isolated from human feces and identified by fluorescent amplified fragment length polymorphism and pheS sequence analyses as Enterococcus faecium strains. Some strains from culture collections belonging to the species E. durans, E. avium, E. faecium, and Lactobacillus reuteri were also able to perform this transformation. Yeast extract, special peptone, and meat extract supported PhIP transformation by the enriched E. faecium strains, while tryptone, monomeric sugars, starch, and cellulose did not. Glycerol was identified as a fecal matrix constituent required for PhIP transformation. Abiotic synthesis of PhIP-M1 and quantification of the glycerol metabolite 3-hydroxypropionaldehyde (3-HPA) confirmed that the anaerobic fermentation of glycerol via 3-HPA is the critical bacterial transformation process responsible for the formation of PhIP-M1. Whether it is a detoxification is still a matter of debate, since PhIP-M1 has been shown to be cytotoxic toward Caco-2 cells but is not mutagenic in the Ames assay.Diet is a major risk factor in human cancer (14). Epidemiological studies indicate that the consumption of cooked meat and meat products predisposes individuals to neoplastic disease, particularly of the colon (13). Cooked muscle meats contain potent genotoxic carcinogens belonging to the heterocyclic aromatic amine (HAA) class of chemical compounds (31). Of the 19 heterocyclic amines identified so far, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) is the most mass-abundant heterocyclic amine produced during the cooking of beef, pork, and chicken (15, 40). Experimentally, PhIP is a potent mutagen and genotoxin and has been shown to produce mammary gland, prostate, and colon tumors in rats (23, 39). For humans, less is known about the potential role of PhIP and related heterocyclic amines in tumor development. Several studies have shown that individuals who eat "well-done" meat have an increased risk of breast (52) and colorectal (18) cancers.To determine the potential health risks associated with heterocyclic amines, several dietary studies have been conducted on the metabolism and disposition of these compounds in humans. So far, most investigations have focused on the activation and ...

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PhIP metabolites in human urine after consumption of well-cooked chicken

Cited by 42 publications

References 62 publications

UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver

UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver

Interspecies metabolism of heterocyclic aromatic amines and the uncertainties in extrapolation of animal toxicity data for human risk assessment

Isolation and Characterization of Human Intestinal Bacteria Capable of Transforming the Dietary Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5- b ]Pyridine

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