In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N-nitrosopyrrolidine, 2-amino-3-methylimidazo[4,5-f]quinoline, and di(2-ethylhexyl)phthalate.
In order to cast light on carcinogen-specific molecular mechanisms underlying experimental hepatocarcinogenesis in rats, in vivo mutagenicity and mutation spectra of known genotoxic rat hepatocarcinogens N-nitrosopyrrolidine (NPYR), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), as well as the nongenotoxic hepatocarcinogen di(2-ethylhexyl)phthalate (DEHP) and the noncarcinogen acetaminophen (AAP), were investigated in guanine phosphoribosyltransferase (gpt) delta transgenic rats, a recently developed animal model for genotoxicity analysis. After 13-wk treatment, glutathione S-transferase placental form (GST-P)-positive liver cell foci were significantly increased in NPYR-treated and IQ-treated rats. In the DEHP-treated rats, marked hepatomegaly with centrilobular hypertrophy of hepatocytes occurred, although GST-P staining was consistently negative. Positive mutagenicity was detected in IQ- and NPYR-treated rats. Mutant frequencies (MFs) in the liver DNA were 188.0 x 10(-6) and 56.5 x 10(-6), approximately 35-fold and 10-fold higher, respectively, than that of nontreatment control rats (5.5 x 10(-6)). There were no increases in MFs in the DEHP- or AAP-treated rats as compared to the nontreatment control value. IQ induced mainly base substitutions leading to G:C to T:A transversions (56.9%) and deletions of G:C base pairs. In contrast, NPYR primarily caused specific A:T to G:C transitions (49.3%), which are very rare in the other groups. These data provided support for the conclusion that IQ and NPYR hepatocarcinogenesis depends on genotoxic processes and specific DNA adduct formation while DEHP exerts its influence via a nongenotoxic promotional pathway. Our data also indicate that analysis of specific in vivo mutational responses with transgenic animal models can provide crucial information for understanding the molecular mechanisms underlying chemical carcinogenesis.
Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
Keita
K
Kanki
Akiyoshi
A
Nishikawa
Ken-Ichi
K
Masumura
Takashi
T
Umemura
Takayoshi
T
Imazawa
Yasuki
Y
Kitamura
Takehiko
T
Nohmi
Masao
M
Hirose
D000818:Animals; D030801:Animals, Genetically Modified; D002273:Carcinogens / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D004252:DNA Mutational Analysis; D004051:Diethylhexyl Phthalate / Q000494:pharmacology*; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology; D009153:Mutagens / Q000494:pharmacology*; D009154:Mutation; D009242:N-Nitrosopyrrolidine / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats
D002273:Carcinogens; D009153:Mutagens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D004247:DNA; D004051:Diethylhexyl Phthalate; D009242:N-Nitrosopyrrolidine