Strain differences of rats in the susceptibility to aberrant crypt foci formation by 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine: no implication of Apc and Pla2g2a genetic polymorphisms in differential susceptibility.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant mutagenic heterocyclic amine contained in cooked food, induces colon tumors in F344 male rats when administered orally. In the present study, PhIP was introduced to various rat strains, and susceptibility to the induction of aberrant crypt foci (ACFs) was analyzed as a biomarker for colon carcinogenesis. BUF/Nac rats were highly susceptible, giving rise to 12.2 +/- 1.7 ACFs per rat. F344 rats were intermediate and ACI/N rats were resistant, giving 3.5 +/- 1.8 and 0.9 +/- 0.7 ACFs per rat, respectively. In spite of this, the extent of DNA damage by PhIP in F344, in terms of the level of PhIP-DNA adducts, was significantly lower than that in ACI/N. The differences in formation of ACFs could be, in some part, implicated in the differential susceptibility to colon carcinogenesis induced by PhIP, especially in a step later than adduct formation. In an attempt to determine the genetic factors implicated in the susceptibility to formation of ACFs, a possible involvement of the adenomatous polyposis gene (Apc) and its modifier secretory phospholipase A2 (Pla2g2a) was analyzed. No genetic polymorphisms in either Apc or Pla2g2a showed a significant correlation to susceptibility to formation of ACFs among rat strains.
Ishiguro
Y
Y
Biochemistry and Carcinogenesis Divisions, National Cancer Center Research Institute, 1-1 Tsukiji 5, Chuo-ku, Tokyo 104-0045, Japan.
Ochiai
M
M
Sugimura
T
T
Nagao
M
M
Nakagama
H
H
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics*; D018736:DNA Adducts / Q000378:metabolism; D017931:DNA Primers; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D054501:Group II Phospholipases A2; D007093:Imidazoles / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D010741:Phospholipases A / Q000235:genetics*; D054467:Phospholipases A2; D011110:Polymorphism, Genetic; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics*; D051381:Rats; D013045:Species Specificity
D002273:Carcinogens; D018736:DNA Adducts; D017931:DNA Primers; D007093:Imidazoles; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; C516289:Pla2g2a protein, rat