Lack of elevated liver carcinogenicity of aminophenylnorharman in p53-deficient mice.
The hepatocarcinogenic potential of 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH) was investigated using male and female p53 deficient mice. Incidence of oval cell hyperplasia was 2/14 (14.3%), 14/23 (60.9%), and 2/10 (20%) in p53 nullizygous (-/-), heterozygous (+/-), and wild type (+/+) mice, respectively, exposed to 30 ppm APNH for 15 weeks, while hepatocellular anisonucleosis was observed only in APNH-treated p53 (-/-) mice. At 40 weeks, hepatocellular carcinomas had developed in 16/46 (34.8%) and 10/27 (37.0%) of female p53 (+/-) and (+/+) mice in contrast to only 1/45 (2.2%) and 2/12 (16.7%) in their male counterparts, respectively, without any detectable p53 gene mutations. Dose-dependent APNH-DNA adduct formation and transcriptional induction of CYP 1A1, but not CYP 1A2, was revealed with 7-day APNH treatment using female C57BL/6J mice. These results suggested hepatocarcinogenicity of APNH in mice could be linked to the liver microenvironment including hormonal milieu but independent of p53 expression and p53 gene mutations.
Iidaka
Takeshi
T
Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusaku, Nagoya 464-8681, Japan.
Tsukamoto
Tetsuya
T
Totsuka
Yukari
Y
Hirata
Akihiro
A
Sakai
Hiroki
H
Shirai
Norimitsu
N
Yamamoto
Masami
M
Wakabayashi
Keiji
K
Yanai
Tokuma
T
Masegi
Toshiaki
T
Donehower
Lawrence A
LA
Tatematsu
Masae
M
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects; D018736:DNA Adducts / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D007211:Indoles / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011725:Pyridines / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D018736:DNA Adducts; D007211:Indoles; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D019363:Cytochrome P-450 CYP1A1; C421010:9-(4'-aminophenyl)-9H-pyrido(3,4-b)indole