Metabolism of 2-Amino-3,8-dimethylimidazo[4,5-<i>f</i>]- quinoxaline in Human Hepatocytes:  2-Amino-3-methylimidazo[4,5-<i>f</i>]quinoxaline-8-carboxylic Acid Is a Major Detoxication Pathway Catalyzed by Cytochrome P450 1A2

Langouët, Sophie; Welti, Dieter H.; Kerriguy, Nathalie; Fay, Laurent B.; Huynh-Ba, T.; Markovic, Jovanka; Guengerich, F. Peter; Turesky, Robert J.

doi:10.1021/tx000176e

Cited by 65 publications

(113 citation statements)

References 48 publications

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“…2, bottom) (Lakshmi et al, 2008), the lack of detection of radioactivity associated with IQ indicates that N-acetyl-IQ is absent in the urine of BNFtreated mice. In previous studies by us and others, urinary N-acetylated HCAs were not detected in mice, rats, monkeys, or humans Snyderwine et al, 1992;Kestell et al, 1999;Langouët et al, 2001;Armbrecht et al, 2007;Lakshmi et al, 2008). The liver cytosol also failed to catalyze N-acetylation, suggesting that this reaction is not involved in mouse HCA metabolism.…”

Section: Lakshmi Et Almentioning

confidence: 69%

“…2) but not in rats. The N-demethylated and C-7 hydroxylated metabolites are reported in monkeys and humans (Snyderwine et al, 1992;Langouët et al, 2001). Four of the mouse metabolites-N-glucuronide, 5-O-glucuronide, sulfamate, and 5-sulfate-exhibited MS spectra identical to the corresponding metabolites in rats.…”

Section: Discussionmentioning

confidence: 95%

“…1) (Inamasu et al, 1989;Armbrecht et al, 2007). Oxidation at the 7-position is reported in monkeys and humans (Snyderwine et al, 1992;Langouët et al, 2001). Direct conjugation of the exocyclic amine to form N 2 -glucuronide or sulfamate is another important pathway (Turesky et al, 1986;Inamasu et al, 1989;Luks et al, 1989;Armbrecht et al, 2007).…”

mentioning

confidence: 99%

“…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). 2-Amino-imidazo[4,5-f]quinoline (demethyl-IQ) is mutagenic (Barnes et al, 1985).…”

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confidence: 99%

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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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Section: Lakshmi Et Almentioning

confidence: 69%

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…metabolites, which form DNA adducts considered important for HCA carcinogenesis in various organs (Langouet et al, 2001;Turteltaub et al, 1997;IARC, 1992). Actually, 1.8 to 18 DNA adducts per 10 10 nucleotides have been detected in human organs such as the colon (Totsuka et al, 1996).…”

mentioning

confidence: 99%

Evidence of a Threshold-Effect for 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline Liver Carcinogenicity in F344/DuCrj Rats

et al. 2008

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To estimate potential human risk of exposure to a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a 2-year carcinogenicity test was conducted using male F344 rats administered MeIQx-containing diet at doses of 0 (control), 0.001, 1, and 100 ppm. The lowest dose 0.001 ppm was established as equivalent to the daily intake of this carcinogen in humans (0.2 to 2.6 μg/man/day). Significant decreases of survival rate and body weight gain were observed in rats treated with 100 ppm MeIQx. Histopathological examination revealed significant induction of hepatocellular carcinomas, adenomas, and development of glutathione S-transferase placental form-positive foci with MeIQx at 100 ppm. Moreover, the incidences of Zymbal's glands carcinoma, mammary fibroadenoma, and subcutaneous fibroma were found significantly increased in a 100 ppm MeIQx group. However, no significant induction of altered preneoplastic hepatocellular foci was observed in 0.001 and 1 ppm groups as compared to the controls. 8-Hydroxy-2'-deoxyguanosine levels in the rat liver DNA of the 100 ppm-treated group were not elevated, but MeIQx-DNA adduct formation increased as compared with the 1 ppm case, albeit without significance. No significant induction of any other neoplastic lesions related to the carcinogen administration was found in MeIQx-administered groups except for 100 ppm. These results imply that 1 ppm may be a no-effect level for MeIQx carcinogenesis.

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Heterocyclic Aromatic Amines

Turesky

2008

Process‐Induced Food Toxicants

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Metabolism of 2-Amino-3,8-dimethylimidazo[4,5-f]- quinoxaline in Human Hepatocytes: 2-Amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic Acid Is a Major Detoxication Pathway Catalyzed by Cytochrome P450 1A2

Cited by 65 publications

References 48 publications

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

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

Evidence of a Threshold-Effect for 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline Liver Carcinogenicity in F344/DuCrj Rats

Heterocyclic Aromatic Amines

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