Dose-response studies of MeIQx in rat liver and liver DNA at low doses.
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a heterocyclic amine mutagen found in cooked meats and is carcinogenic in mice and rats at high doses (mg/kg body wt). Humans, however, are exposed to low amounts (p.p.b.) in the diet, and the effects caused by exposure to human equivalent doses of MeIQx have been difficult to determine accurately. We report on the effect of MeIQx exposure on liver bioavailability, hepatic DNA binding and MeIQx persistence in both liver tissue and liver DNA after acute (24 h), and subchronic (7 day and 42 day) exposures in male Sprague-Dawley rats. Male Sprague-Dawley rats were administered [2-14C]MeIQx either by gavage or in the diet for 1, 7 or 42 days (1 x 10(-6) mg/kg day up to 3.4 x 10(-2) mg/kg day dose) and the [2-14C]MeIQx was measured by accelerator mass spectrometry (AMS). Assessment of the kinetics of hepatic MeIQx DNA adduct formation over 42 days (1.1 x 10(-4) mg [2-14C]MeIQx kg daily dose) shows that steady-state [2-14C]MeIQx tissue concentrations of 138 +/- 15 pg/g liver and DNA adduct levels of 113 +/- 10 ag adduct/micrograms DNA were reached at 14-28 days and 28 days respectively. The relationship between administered dose and either hepatic MeIQx DNA adduct levels or MeIQx tissue levels are linear for the 24 h, 7 day and 42 day exposures. Furthermore, MeIQx adducts persist for at least 14 days after exposure ceases. These data suggest that bioavailability and DNA adduction by MeIQx increase linearly with increasing dose for both acute and subchronic exposures. These data also show that MeIQx DNA adducts are useful in predicting daily exposure and support a linear extrapolation in the risk assessment of MeIQx. However, the quantitative relationship between DNA adducts and tumor formation will also depend on the specific tissue and the subsequent steps needed for tumor progression.
Frantz
C E
CE
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, CA 94550.
Bangerter
C
C
Fultz
E
E
Mayer
K M
KM
Vogel
J S
JS
Turteltaub
K W
KW
D000818:Animals; D001682:Biological Availability; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism*; D018736:DNA Adducts / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D009153:Mutagens / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D009711:Nucleotides / Q000378:metabolism; D011810:Quinoxalines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens; D009711:Nucleotides; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D004247:DNA