Macromolecular adduct formation and metabolism of heterocyclic amines in humans and rodents at low doses.
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are heterocyclic amines formed during the cooking of meat and fish. Both are genotoxic in a number of test systems and are carcinogenic in rats and mice. Human exposure to these compounds via dietary sources has been estimated to be under 1 microg/kg body wt. per day, although most laboratory animal studies have been conducted at doses in excess of 10 mg/kg body wt. per day. We are using accelerator mass spectrometry (AMS), a tool for measuring isotopes with attomole sensitivity, to study the dosimetry of protein and DNA adduct formation by low doses of MeIQx and PhIP in rodents and comparing the adduct levels to those formed in humans. The results of these studies show: 1, protein and DNA adduct levels in rodents are dose-dependent; 2, adduct levels in human tissues and blood are generally greater than in rodents administered equivalent doses; and 3, metabolite profiles differ substantially between humans and rodents for both MeIQx and PhIP, with more N-hydroxylation (bioactivation) and less ring oxidation (detoxification) in humans. These data suggest that rodent models do not accurately represent the human response to heterocyclic amine exposure.
Turteltaub
K W
KW
Lawrence Livermore National Laboratory, Livermore, CA 94550, USA. turteltaub2@llnl.gov
Dingley
K H
KH
Curtis
K D
KD
Malfatti
M A
MA
Turesky
R J
RJ
Garner
R C
RC
Felton
J S
JS
Lang
N P
NP
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D011810:Quinoxalines / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats
D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D046911:Macromolecular Substances; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine