Lack of carcinogenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in cynomolgus monkeys.
The carcinogenic potential of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was evaluated in cynomolgus monkeys. The animals received MeIQx, beginning at the age of one year, at doses of 10 or 20 mg/kg body weight by gavage five times a week for 84 months and were autopsied 8 months thereafter. Although sporadic development of aberrant crypt foci in the colon and glutathione S-transferase pi-positive foci in the liver as well as hyperplastic changes of the lymphatic tissue in the lung and gastro-intestinal tract were observed in several monkeys, this was not treatment-related. No neoplastic or preneoplastic lesions were found in other organs. Serum chemistry data and organ weights were also within the normal ranges. From these data, it is concluded that MeIQx is not carcinogenic in the cynomolgus monkey under the conditions examined. This lack of carcinogenicity is probably related to the poor activation of MeIQx due to the lack of constitutive expression of CYP1A2 as well as an inability of other cytochrome P450s to catalyze N-hydroxylation of MeIQx in the cynomolgus monkey.
Ogawa
K
K
Nagoya City University Medical School. kogawa@med.nagoya-cu.ac.jp
Tsuda
H
H
Shirai
T
T
Ogiso
T
T
Wakabayashi
K
K
Dalgard
D W
DW
Thorgeirsson
U P
UP
Thorgeirsson
S S
SS
Adamson
R H
RH
Sugimura
T
T
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology; D018736:DNA Adducts / Q000378:metabolism; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D011810:Quinoxalines / Q000633:toxicity*
D002273:Carcinogens; D018736:DNA Adducts; D007527:Isoenzymes; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D019388:Cytochrome P-450 CYP1A2; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase