MeIQx-DNA adduct formation in rodent and human tissues at low doses.
Heterocyclic amines, such as 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), are mutagenic/carcinogenic compounds formed during the cooking of protein-rich foods. Human exposure to MeIQx has been estimated to range from ng/person/day to a few microgram/person/day. In contrast, animal studies have been conducted at doses in excess of 10 mg/kg/day. In order to determine the relevance of high-dose animal data for human exposure, the dose-response curves for [14C]-MeIQx have been determined in rodents at low doses under both single-dose and chronic dosing regimens using the high sensitivity of accelerator mass spectrometry (AMS). To make a direct species comparison, rodent and human colonic MeIQx-DNA adduct levels have been compared following oral administration of [14C]-MeIQx. The results of these studies show: (1) total MeIQx levels are highest in the liver > kidney > pancreas > intestine > blood; (2) MeIQx levels in the liver plateau after 7 days of chronic feeding; (3) hepatic MeIQx-DNA adducts begin to plateau after 2-4 weeks and reach steady-state levels between 4 and 12 weeks on chronic exposures; (4) hepatic DNA adducts generally increase as a linear function of administered dose for a single-dose exposure and as a power function for chronic feeding over a dose range spanning 4 orders of magnitude; (5) human colon DNA adduct levels are approximately 10 times greater than in rodents at the same dose and time point following exposure; and (6) > or = 90% of the MeIQx-DNA adduct in both rodent and human colon appears to be the dG-C8-MeIQx adduct. These studies show that MeIQx is readily available to the tissues for both humans and rodents and that adduct levels are generally linear with administered dose except at high chronic doses where adduct levels begin to plateau slightly. This plateau indicates that linear extrapolation from high-dose studies probably underestimates the amount of DNA damage present in the tissues following low dose. Further, if adducts represent the biologically effective dose, these data show that human colon may be as sensitive to the genotoxic effects of MeIQx as rat liver. The significance of these endpoints to tumor response remains to be determined.
Turteltaub
K W
KW
Lawrence Livermore National Laboratory, Livermore, CA 94550, USA. turteltaub2@llnl.gov
Mauthe
R J
RJ
Dingley
K H
KH
Vogel
J S
JS
Frantz
C E
CE
Garner
R C
RC
Shen
N
N
D000818:Animals; D003110:Colonic Neoplasms / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005069:Evaluation Studies as Topic; D006801:Humans; D008099:Liver / Q000378:metabolism; D011810:Quinoxalines / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D018736:DNA Adducts; D011810:Quinoxalines; C085470:2-amino-4-hydroxymethyl-3,8-dimethylimidazo(4,5-f)quinoxaline