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

Journal Article · 25 February 2016 · Chemical Research in Toxicology

DOI: https://doi.org/10.1021/acs.chemrestox.5b00495 · OSTI ID:1282119

Malfatti, Michael A. ^[1]; Kuhn, Edward A. ^[1]; Turteltaub, Kenneth W. ^[1]; Vickers, Selwyn M. ^[2]; Jensen, Eric H. ^[3]; Strayer, Lori ^[3]; Anderson, Kristin E. ^[3]

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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)

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.

• Research Organization: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
• Sponsoring Organization: National Inst. of General Medical Sciences; USDOE
• Grant/Contract Number: AC52-07NA27344
• OSTI ID: 1282119
• Report Number(s): LLNL-JRNL-679828
• Journal Information: Chemical Research in Toxicology, Journal Name: Chemical Research in Toxicology Journal Issue: 3 Vol. 29; ISSN 0893-228X
• Publisher: American Chemical Society (ACS)Copyright Statement
• Country of Publication: United States
• Language: English