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Title: Disposition of the Dietary Mutagen 2-Amino-3,8-dimethylimidazo[4,5- f ]quinoxaline in Healthy and Pancreatic Cancer Compromised Humans

Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the U.S. Once diagnosed, prognosis is poor with a 5-year survival rate of less than 5%. Exposure to carcinogenic heterocyclic amines (HCAs) derived from cooked meat has been shown to be positively associated with pancreatic cancer risk. To evaluate the processes that determines the carcinogenic potential of HCAs for human pancreas, 14-carbon labeled 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a putative human carcinogenic HCA found in well-done cooked meat, was administered at a dietary relevant dose to human volunteers diagnosed with pancreatic cancer undergoing partial pancreatectomy and healthy control volunteers. After 14C-MeIQx exposure, blood and urine was collected for pharmacokinetic and metabolite analysis. MeIQx-DNA adducts levels were quantified by accelerator mass spectrometry from pancreatic tissue excised during surgery from the cancer patient group. Pharmacokinetic analysis of plasma revealed a rapid distribution of MeIQx with a plasma elimination half-life of approximately 3.5 hr in 50% of the cancer patients and all of the control volunteers. In 2 of the 4 cancer patients very low levels of MeIQx were detected in plasma and urine suggesting low absorption from the gut into the plasma. Urinary metabolite analysis revealed five MeIQx metabolites with 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid being themore » most abundant accounting for 25%–50% of the recovered 14-carbon/ml urine. We found there was no discernable difference in metabolite levels between the cancer patient volunteers and the control group. MeIQx-DNA adduct analysis of pancreas and duodenum tissue revealed adduct levels indistinguishable from background levels. Lastly, although other meat-derived HCA mutagens have been shown to bind DNA in pancreatic tissue, indicating that exposure to HCAs from cooked meat cannot be discounted as a risk factor for pancreatic cancer, the results from this current study show that exposure to a single dietary dose of MeIQx does not readily form measurable DNA adducts under the conditions of the experiment.« less

Authors:
 [1];  [1];  [1];  [2];  [3];  [3];  [3]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biosciences and Biotechnology Division
  2. Univ. of Alabama, Birmngham, AL (United States)
  3. Univ. of Minnesota, Minneapolis, MN (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE; National Inst. of General Medical Sciences
OSTI Identifier:
1282119
Alternate Identifier(s):
OSTI ID: 1367983
Report Number(s):
LLNL-JRNL-679828
Journal ID: ISSN 0893-228X
Grant/Contract Number:
AC52-07NA27344; P50 CA101955-07; 2P41GM103483-16
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Chemical Research in Toxicology
Additional Journal Information:
Journal Volume: 29; Journal Issue: 3; Journal ID: ISSN 0893-228X
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Malfatti, Michael A., Kuhn, Edward A., Turteltaub, Kenneth W., Vickers, Selwyn M., Jensen, Eric H., Strayer, Lori, and Anderson, Kristin E. Disposition of the Dietary Mutagen 2-Amino-3,8-dimethylimidazo[4,5- f ]quinoxaline in Healthy and Pancreatic Cancer Compromised Humans. United States: N. p., 2016. Web. doi:10.1021/acs.chemrestox.5b00495.
Malfatti, Michael A., Kuhn, Edward A., Turteltaub, Kenneth W., Vickers, Selwyn M., Jensen, Eric H., Strayer, Lori, & Anderson, Kristin E. Disposition of the Dietary Mutagen 2-Amino-3,8-dimethylimidazo[4,5- f ]quinoxaline in Healthy and Pancreatic Cancer Compromised Humans. United States. doi:10.1021/acs.chemrestox.5b00495.
Malfatti, Michael A., Kuhn, Edward A., Turteltaub, Kenneth W., Vickers, Selwyn M., Jensen, Eric H., Strayer, Lori, and Anderson, Kristin E. Fri . "Disposition of the Dietary Mutagen 2-Amino-3,8-dimethylimidazo[4,5- f ]quinoxaline in Healthy and Pancreatic Cancer Compromised Humans". United States. doi:10.1021/acs.chemrestox.5b00495. https://www.osti.gov/servlets/purl/1282119.
@article{osti_1282119,
title = {Disposition of the Dietary Mutagen 2-Amino-3,8-dimethylimidazo[4,5- f ]quinoxaline in Healthy and Pancreatic Cancer Compromised Humans},
author = {Malfatti, Michael A. and Kuhn, Edward A. and Turteltaub, Kenneth W. and Vickers, Selwyn M. and Jensen, Eric H. and Strayer, Lori and Anderson, Kristin E.},
abstractNote = {Pancreatic cancer is the fourth leading cause of cancer death in the U.S. Once diagnosed, prognosis is poor with a 5-year survival rate of less than 5%. Exposure to carcinogenic heterocyclic amines (HCAs) derived from cooked meat has been shown to be positively associated with pancreatic cancer risk. To evaluate the processes that determines the carcinogenic potential of HCAs for human pancreas, 14-carbon labeled 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a putative human carcinogenic HCA found in well-done cooked meat, was administered at a dietary relevant dose to human volunteers diagnosed with pancreatic cancer undergoing partial pancreatectomy and healthy control volunteers. After 14C-MeIQx exposure, blood and urine was collected for pharmacokinetic and metabolite analysis. MeIQx-DNA adducts levels were quantified by accelerator mass spectrometry from pancreatic tissue excised during surgery from the cancer patient group. Pharmacokinetic analysis of plasma revealed a rapid distribution of MeIQx with a plasma elimination half-life of approximately 3.5 hr in 50% of the cancer patients and all of the control volunteers. In 2 of the 4 cancer patients very low levels of MeIQx were detected in plasma and urine suggesting low absorption from the gut into the plasma. Urinary metabolite analysis revealed five MeIQx metabolites with 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid being the most abundant accounting for 25%–50% of the recovered 14-carbon/ml urine. We found there was no discernable difference in metabolite levels between the cancer patient volunteers and the control group. MeIQx-DNA adduct analysis of pancreas and duodenum tissue revealed adduct levels indistinguishable from background levels. Lastly, although other meat-derived HCA mutagens have been shown to bind DNA in pancreatic tissue, indicating that exposure to HCAs from cooked meat cannot be discounted as a risk factor for pancreatic cancer, the results from this current study show that exposure to a single dietary dose of MeIQx does not readily form measurable DNA adducts under the conditions of the experiment.},
doi = {10.1021/acs.chemrestox.5b00495},
journal = {Chemical Research in Toxicology},
number = 3,
volume = 29,
place = {United States},
year = {Fri Feb 26 00:00:00 EST 2016},
month = {Fri Feb 26 00:00:00 EST 2016}
}

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  • Mutagenic activity of the cooked-food mutagen/carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is highly dependent upon cytochrome P450 activation to the N-hydroxylated intermediate. The present study investigated the bioactivation pathways of PhIP in Salmonella typhimurium and isolated rat hepatocyte preparations. In the Ames/S. typhimurium assay, the acetyltransferase and sulfotransferase enzyme inhibitors pentachlorpophenol (PCP) and 2,6-dichloro-4-nitrophenol (DCNP) were used to modulate mutagenicity. DCNP, but not PCP, produced a concentration-dependent decrease in mutagenic activity of 2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-hydroxy-PhIP). In rat hepatocyte preparations, PCP and DCNP, as well as the cytochrome P450 IA1 and IA2 inhibitor [alpha]-naphthoflavone (ANF), were used to modulate metabolite, protein adduct, and DNA adductmore » formation. Incubations of [[sup 3]H]PhIP (100 [mu]M) with Aroclor 1254-induced or uninduced hepatocytes resulted in the formation of several metabolites, including 4[prime]-(2-amino-1-methylimidazo[4,5-b]pyrid-6-yl)phenyl sulfate (4[prime]-PhIP-sulfate), 2-amino-1-methyl-4[prime]-hydroxy-6-phenylimidazo[4,5-b]pyridine, and other uncharacterized metabolites. While PCP or DCNP pretreatment produced a significant decline in sulfate-dependent conjugation of 4[prime]-hydroxy-PhIP to 4[prime]-PhIP-sulfate, these inhibitors produced only slight decreases in PhIP-dependent covalent binding to proteins in hepatocytes derived from either Aroclor 1254-induced or uninduced rats. PhIP DNA adduct levels were relatively unchanged by PCP or DCNP pretreatment of Aroclor 1254-induced hepatocytes. DNA adducts from hepatocytes dosed with N-hydroxy-PhIP, however, resulted in a decrease in adduct levels from cells pretreated with PCP or DCNP. Pretreatment of cells with ANF reduced the formation of all detectable metabolites by at least 50%, yet increased DNA adduct levels by nearly 4-fold. 36 refs., 6 figs., 2 tabs.« less
  • Phosphorescence intensities and lifetimes of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and benzo[f]quinoline (B[f]Q) in glucose glasses were measured over a wide range of temperatures. As the temperature decreased, both the phosphorescence lifetimes and the phosphorescence intensities for PhIP and B[f]Q in glucose glasses increased. However, the phosphorescence intensity-to-lifetime ratio was not constant at different temperatures, which indicated that the triplet state formation efficiency was a function of temperature. Also, the In (1/{tau}{sub p} - 1{tau}{sub p0}) vs 1/T plots for both PhIP and B[f]Q in glucose glasses with and without a heavy-atom salt gave nonlinear plots. From the plots for the samples withmore » and without a heavy-atom salt, activation energies were obtained. The activation energies were related to low-frequency vibrational modes in the solid matrix, rotational relaxation of functional groups, and diffusion of water in the solid matrix. Infrared spectrometry revealed water in the glasses, and phosphorescence decay curves and confocal laser scanning microscopy showed the heterogeneity of the distribution of NaI in the glucose glasses. 34 refs., 4 figs., 3 tabs.« less
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