TY - JOUR
T1 - Lack of elevated liver carcinogenicity of aminophenylnorharman in p53-deficient mice
AU - Iidaka, Takeshi
AU - Tsukamoto, Tetsuya
AU - Totsuka, Yukari
AU - Hirata, Akihiro
AU - Sakai, Hiroki
AU - Shirai, Norimitsu
AU - Yamamoto, Masami
AU - Wakabayashi, Keiji
AU - Yanai, Tokuma
AU - Masegi, Toshiaki
AU - Donehower, Lawrence A.
AU - Tatematsu, Masae
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare, Japan and a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
PY - 2005/1/20
Y1 - 2005/1/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=19944393208&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=19944393208&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2004.07.015
DO - 10.1016/j.canlet.2004.07.015
M3 - Article
C2 - 15617832
AN - SCOPUS:19944393208
SN - 0304-3835
VL - 217
SP - 149
EP - 159
JO - Cancer Letters
JF - Cancer Letters
IS - 2
ER -
