Susceptibility of Liver Proliferative Lesions in Heterozygous p53 Deficient CBA Mice to Various Carcinogens.

Abstract

ABSTRACT. To investigate the liver tumorigenic sensitivity to various carcinogens in heterozygous p53 deficient [p53 (+/-)] CBA mice and their wild-type littermates [p53 (+/+) mice], 71 p53 (+/-) and 74 p53 (+/+) CBA mice (male, 6-12 weeks of age) were given diet containing 4,000 or 0 ppm flumequine (FL) for 26 weeks or a single intraperitoneal injection of 5 mg/kg body weights dimethylnitros amine (DMN) at start of the study in Exp. 1, diet containing 6,000 or 0 ppm di(2-ethylhexyl)-phthalate (DEHP) for 26 weeks in Exp. 2, or diet containing 12,000, 6,000 or 0 ppm phenolphthalein (PhP) for 26 weeks in Exp. 3. All surviving animals of these groups were killed after completion of treatment of the test substances for 26 weeks. In the FL groups, the incidences of hepatocellular altered f oci in p53 (+/-) mice, the multiplicities of those in p53 (+/-) and p53 (+/+) mice were significantly increased as compared to the corresponding control groups. The incidences and multiplicities of altered foci in the DMN groups were higher than those in the corresponding control groups in p53 (+/-) and p53 (+/+) mice, but no significant differences were indicated between the groups. There were no significant differences in the incidences, multiplicities and proliferating cell nuclear antigen labeling indices of altered foci in the FL or DMN groups between p53 (+/-) and p53 (+/+) mice. There were no significant differences in the incidences and multiplicities of altered foci between the DEHP or PhP and control groups. The present results suggest that p53 gene knocked out heterozygously does not enhance the chemical hepatocarcinogenesis in CBA mice. KEY WORDS: dimethylnitrosamine, di(2-ethylhexyl)-phthalate, flumequine, phenolphthalein, p53 (+/-) CBA mouse.

C3H/He Mice as an Incompatible Cholangiocarcinoma Model by <i>Clonorchis sinensis</i>, Dicyclanil and N-Nitrosodimethylamine

“…An earlier study showed that about 2 mg/kg/day dose of NDMA to C3H/He mice for 32 days causes promutagenic DNA lesion (O 6 -methylguanine) [ 17 ]. In a study, CBA mice were subjected to a single dose of NDMA (5 mg/kg) and kept the animals for 26 weeks but any apparent hepatocellular tumor was not observed [ 18 ]. In a liver fibrosis study, ICR strains of mice were subjected to 8 mg/kg dose of NDMA for 15 days at regular intervals (totaling 120 mg/kg) [ 19 ].…”

Induction of Hepatocellular Proliferative Lesions in CBA Mice by a 26-week Dietary Administration of Kojic Acid

“…In our previous 26-week study in which DEHP or PhP was administered to each male p53 (+/-) and p53 (+/+) mice, hepatocellular altered foci were detected in the control animals. The incidence of this type of lesion in the control p53 (+/-) mice receiving DEHP was approximately 22%, while the incidences of the same type of lesion in the control p53 (+/-) and p53 (+/+) mice receiving PhP were approximately 33 and 26%, respectively 11 . In addition, Takizawa et al (2003) reported that focal necrosis of hepatocytes occurred in control p53 (+/+) mice in a 26-week study administering KA 10 .…”

“…Smith et al (1973) reported that the spontaneous incidences of lymphoma in CBA mice were 6% in males and 15% in females of CBA strain 12 . In our previous 26-week study using p53 (+/-) and p53 (+/+) mice, a dead animal due to malignant lymphoma was found during the treatment period 11 . Furthermore, the incidences of death were not dose-dependent in the present study, therefore, these deaths were considered not to be attributable to the KA treatment.…”

Susceptibility of Heterozygous and Nullizygous p53 Knockout Mice to Chemical Carcinogens: Tissue Dependence and Role of p53 Gene Mutations

“…In particular, activating mutations in the β-catenin gene are thought to be responsible for the excess β-catenin signaling featured in the majority of carcinogen-induced colonic lesions 67 , including small foci 68 . Mammary carcinogenesis induced by DMBA 16 and hepatocarcinogenesis initiated with the genotoxic carcinogens dimethylnitrosamine (DMN), 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), 6-nitrochrysene (6-NC) 69 , 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) 70 , DEN 15 , and other chemicals 71 including APNH, a novel heterocyclic amine 19 , may reflect organ/tissue specificity in the threshold for the p53 gene product. While the mechanism may involve an additional hit to inactivate the second normal allele, Venkatachalam et al 55 have proposed that reduction of the p53 gene products may be sufficient to promote tumorigenesis.…”