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

Michael A. Malfatti, Edward A. Kuhn, Kenneth W. Turteltaub, Selwyn M. Vickers, Eric H. Jensen, Lori Strayer, Kristin E. Anderson

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 determine 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 were 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 h 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. There was no discernible 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. 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.

Original languageEnglish (US)
Pages (from-to)352-358
Number of pages7
JournalChemical research in toxicology
Volume29
Issue number3
DOIs
StatePublished - Mar 21 2016

Bibliographical note

Funding Information:
This work was performed under the auspices of the U.S. Department of Energy by, Lawrence Livermore National Laboratory at the Research Resource for Biomedical AMS under contract DE-AC52-07NA27344 and supported by a grant from the National Institute of General Medical Sciences (2P41GM103483-16). Support was also provided through a pilot funding mechanism from UAB/UMN SPORE in Pancreatic Cancer (NIH/NCI P50 CA101955-07). We thank the following individuals for their contributions to this research: Gerri Anderson and Danielle Jin for assistance in study logistics and subject recruitment; Bruce Lindgren for statistical advice and Dr. Myron Gross for sample storage; Dr. Robert Turesky for providing the MeIQx metabolite standards; and Dr. Ted Ognibene and Elise Hill for AMS sample analysis. The late Dr. Fred Kadlubar contributed to the design and planning of this project.

Publisher Copyright:
© 2016 American Chemical Society.

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