Metabolism of the Food-Borne Mutagen 2-Amino-3,8-dimethylimidazo[4,5-<i>f</i>]quinoxaline in Humans

Turesky, Robert J.; Garner, R. Colin; Welti, Dieter H.; Richoz, Janique; Leveson, Stephen H.; Dingley, Karen H.; Turteltaub, Kenneth W.; Fay, Laurent B.

doi:10.1021/tx9701891

Cited by 64 publications

(92 citation statements)

References 40 publications

(110 reference statements)

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“…The major pathways of metabolism of 8-MeIQx and PhIP in humans and urinary excretion products have been well characterized; however, the metabolic pathways of AaC are unknown (48)(49)(50). Both 8-MeIQx and PhIP undergo oxidation by cytochrome P450s or undergo direct conjugation by UDPglucuronosyltransferases or sulfotransferases, to form conjugates at the exocyclic amino groups of both HAAs and at the N3 imidazole atom of PhIP (48,50).…”

Section: Discussionmentioning

confidence: 99%

“…Both 8-MeIQx and PhIP undergo oxidation by cytochrome P450s or undergo direct conjugation by UDPglucuronosyltransferases or sulfotransferases, to form conjugates at the exocyclic amino groups of both HAAs and at the N3 imidazole atom of PhIP (48,50). The excretion of unmetabolized 8-MeIQx and PhIP in urine of male subjects in Western Europe and the United States, who ate well-done beef, was reported at, respectively, about 2% to 5% and 0.5% to 2% of the dose within 10 h after consumption of well-done fried beef (27,33,45).…”

Section: Discussionmentioning

confidence: 99%

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Tobacco Smoking and Urinary Levels of 2-Amino-9H-Pyrido[2,3-b]Indole in Men of Shanghai, China

Turesky

Yuan²,

Wang

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Carcinogenic heterocyclic aromatic amines (HAA) are formed in cooked meats, poultry, and fish and arise in tobacco smoke. We measured the concentrations of four prevalent HAAs in spot urine samples collected at baseline from 170 participants of the Shanghai Cohort study, a population-based cohort study of adult men recruited during 1986 to 1989 in Shanghai, China. Sixteen (18.6%) of 86 nonsmokers were positive for urinary 2-amino-9H-pyrido[2,3-b]indole (AAC) versus 41 (48.8%) of 84 cigarette smokers; the difference was statistically significant (P < 0.001). The number of cigarettes smoked per day was positively and significantly related to urinary levels of AAC in study subjects (P < 0.001); the mean level among nonsmokers was 2.54 ng/g creatinine, whereas the means for light (1-19 cigarettes per day) and heavy (20+ cigarettes per day) smokers were 7.50 and 11.92 ng/g creatinine, respectively. 2-Amino-3,4,8-trimethylimidazo [4,5-f] quinoxaline was undetected in the urine of the 170 subjects. Only 5 (2.9%) and 6 (3.5%) subjects, respectively, showed detectable levels of urinary 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline, and smoking status was unrelated to levels of either HAA. Quantitative measurements of HAAs in commonly eaten pork and chicken dishes in Shanghai showed low concentrations of HAAs (<1 ng/g meat). Our data indicate that AAC represents a major HAA exposure in adult men of Shanghai, China, and that tobacco smoke is an important point source of their AAC exposure. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1554 -60)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tobacco Smoking and Urinary Levels of 2-Amino-9H-Pyrido[2,3-b]Indole in Men of Shanghai, China

Turesky

Yuan²,

Wang

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Human CYP1A2 is regioselective for the N-oxidation of HAAs, such as IQ, MeIQx, and PhIP (bioactivation), and does not catalyze the oxidation (detoxication) of the heteroaromatic ring systems [42,53,59]. Human CYP1A2 also catalyzes the three-step oxidation of the C 8 -methyl group of 8-MeIQx to form the car- boxylic acid derivative, 2-amino-3-methylimidazo[4,5-f]-quinoxaline-8-carboxylic acid [27,60], a major pathway of detoxication 8-MeIQx in vivo [42]. This oxidation pathway is specific for human CYP1A2, and CYPs of rodents and nonhuman primates do not form this product [24,41].…”

Section: Species Differences In Regioselectivity Of Cyp1a2-catalyzed mentioning

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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“…For example, several studies in humans have detected HCA metabolites, which are not present in rats and have not yet been identified (Turesky et al, 1998;Garner et al, 1999;Langouët et al, 2001). In addition, N-demethylation is a primary pathway for HCA in humans (Langouët et al, 2001) and monkeys (Snyderwine et al, 1992) but is not detected in rats (Armbrecht et al, 2007;Lakshmi et al, 2008).…”

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Identification of New 2-Amino-3-methylimidazo[4,5-f]quinoline Urinary Metabolites from β-Naphthoflavone-Treated Mice

Lakshmi

Hsu²,

Zenser

2009

Drug Metab Dispos

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Cancer etiology and human risk estimates suggest that our diet contains mutagenic and carcinogenic chemicals that are agents in human cancer. Examples of these agents are aflatoxin B 1 , which is formed by fungi growing on poorly stored grain and associated with liver cancer (Groopman et al., 1988). Benzo[a]pyrene, a product of incomplete combustion of organic material, can deposit on food from fat dripping onto the coals during cooking or as a result of charring of food. These and other polycyclic aromatic hydrocarbons have been associated with several types of tumors (IARC, 1983). Heterocyclic amines (HCAs) are another class of dietary carcinogens (Felton and Knize, 1990). These chemicals are produced by high-temperature cooking of meat and derived from amino acids, creatine, and glucose present in meat. More than 17 different HCAs have been isolated from cooked meat. Studies have identified breast, colon, and bladder as possible target organs of HCAs and recently designated 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) as "reasonably anticipated to be a human carcinogen" (National Toxicology Program Report on Carcinogens: Background Document for Heterocyclic Amines: MeIQ, MeIQx, IQ, and PhIP, 2005; http://ntp.niehs.nih.gov/ntp/roc/eleventh/ profiles/s092vhca.pdf).IQ is an HCA. Studies in nonhuman primates given IQ showed a 95% incidence of hepatocarcinomas (Adamson et al., 1994). Additional studies in mice and rats have shown tumor formation in multiple tissues (Sugimura, 2000). Exposure to HCAs varies depending on cooking techniques, temperature, time, and the type and amount of meat consumed with individuals potentially exposed to micrograms of these amines per day (Felton and Knize, 1990;Pais et al., 1999). Current knowledge underlying the mechanism of HCA carcinogenesis indicates interplay of activation and detoxification pathways.IQ activation requires N-oxidation by cytochrome P450 (P450), followed by O-acetylation with subsequent formation of a reactive intermediate, nitrenium ion, which binds DNA and initiates carcinogenesis (Turesky et al., 1991). N-OH-IQ is detected as a microsomal oxidation product (Turesky et al., 1991) but is not detected in urine because of its lability. Bacteria expressing human P450 1A2 and N-acetyltransferase activate IQ to a mutagen(s), mimicking the in vivo

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Metabolism of the Food-Borne Mutagen 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline in Humans

Cited by 64 publications

References 40 publications

Tobacco Smoking and Urinary Levels of 2-Amino-9H-Pyrido[2,3-b]Indole in Men of Shanghai, China

Tobacco Smoking and Urinary Levels of 2-Amino-9H-Pyrido[2,3-b]Indole in Men of Shanghai, China

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

Identification of New 2-Amino-3-methylimidazo[4,5-f]quinoline Urinary Metabolites from β-Naphthoflavone-Treated Mice

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