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This content will become publicly available on February 26, 2017

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

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:
OSTI Identifier:
1282119
Grant/Contract Number:
AC52-07NA27344; P50 CA101955-07; 2P41GM103483-16
Type:
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)
Research Org:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org:
USDOE; National Inst. of General Medical Sciences
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES