Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cigarette smoking has been established as a risk factor for the development of cervical cancer. Polycyclic aromatic hydrocarbons such as benzo[a]pyrene (B[a]P), which are present in cigarette smoke, might account for this increased risk. The effects of B[a]P on cell growth, aryl hydrocarbon hydroxylase, DNA adducts and p53 levels was measured in cervical cells. Since 90% of cervical preneoplastic lesions are positive for the human papillomavirus (HPV) we compared the effects of these chemicals in normal ectocervical epithelial cells (ECE) and human papillomavirus 16 (HPV16) immortalized ectocervical epithelial cells (ECE16-1). Exposure of normal ECE and HPV immortalized ECE16-1 cells to B[a]P inhibited cell proliferation. Inhibition occurred at 20-fold lower concentrations in the normal ECE cells compared to ECE16-1 cells. The proliferation of cervical cells which express mutated p53 was unaffected by B[a]P. Neither cervical stromal cells nor endometrial stromal cells were affected by these compounds. The effects of B[a]P on normal ECE cell proliferation correlated with increased terminal differentiation as measured by increased envelope formation. In contrast, B[a]P exposure did not induce envelope formation in immortalized ECE16-1 cells or in cervical tumor cells. Pretreatment of both ECE and ECE16-1 cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin, which induces P450 expression and activity, did not alter B[a]P metabolism in either normal or immortalized cells. Furthermore, equivalent levels of DNA adducts were formed by B[a]P in ECE and ECE16-1 cells. Neither the extent of adduct formation nor the rate of their removal differed in normal and immortalized cervical cells. Therefore, the diminished growth inhibition of the ECE16-1 cells as compared to normal ECE cells by B[a]P is not due to changes in cytochrome P450 of the 1A family metabolism or DNA adduct number. Furthermore, analysis of the p53 levels in both normal and ECE16-1 cells revealed that p53 levels are higher in normal versus immortalized ectocervical cells, and p53 is induced in both cell types following B[a]P treatment. Thus reduced p53 levels in ECE16-1 cells may contribute to a lack of growth suppression following B[a]P treatment. These results demonstrate that HPV16 immortalization diminishes ectocervical epithelial cell responsiveness to toxicant damage (i.e. decreased cell proliferation and increased terminal differentiation). As a result, ECE16-1 cells that sustain genotoxic damage which leads to DNA adduct formation continue to proliferate and may be at increased risk for mutations and further progression towards a fully transformed phenotype.
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PMID:Differential response of normal and HPV immortalized ectocervical epithelial cells to B[a]P. 758 44

Our prior studies have shown that single topical treatment of repeated fish fried oil extract (RFFE), containing various polycyclic aromatic hydrocarbons (PAHs), to the dorsal epidermis of mice caused enhancement of DNA damage along with higher expression of p53 and p21WAF1 proteins and cell-cycle arrest. In the present study carcinogenic potential of repeated fish fried oil (RFFO) and RFFE was assessed. Single topical application of RFFO (100 microL/animal) and RFFE (100-500 microg/animal) to Swiss albino female mice resulted in significant induction (1.8- to 7.4-fold) of ornithine decarboxylase activity. Twice weekly topical application of methylcholanthrene (MCA) for 24 wk or single topical application of 7,12-dimethylbenzanthracene (DMBA) or RFFO or RFFE, as initiator followed by twice weekly application of 12-O-tetradecanoyl phorbol myristate acetate (TPA) as promoter for 24 wk, resulted in development of skin papillomas after 6, 7, 18, and 9 wk, respectively. The cumulative number of tumors in MCA, DMBA/TPA, RFFE (200 microg)/TPA, and RFFE (500 microg)/TPA groups were 276, 168, 34, and 58 after 24 wk while negligible or minimal initiating activity was noticed in RFFO/TPA group. No tumors were found in animals either given twice weekly topical application of RFFO or a single initiating dose of DMBA followed by twice weekly application of RFFO. Histopathology of skin of animals treated with RFFE/TPA showed marked proliferation of epidermal layers along with abnormal mitosis and multinucleated tumor appearance. Skin of animals in groups RFFO/TPA and DMBA/RFFO showed sloughing and regeneration of epidermal layers, oedema along with proliferation of fibroblasts. Histochemical localization of gamma-glutamyl transpeptidase was found to be substantially higher in skin of mice treated with RFFO/TPA and RFFE/TPA. Animals treated with RFFO/TPA, DMBA/RFFO, and RFFE/TPA resulted in significant induction of cutaneous aryl hydrocarbon hydroxylase (AHH) (421-432%), ethoxyresorufin-O-deethylase (252-316%), and glutathione S-transferase (133-245%) activities. Animals treated with RFFO/TPA, DMBA/RFFO, and RFFE/TPA led to significant reduction in glutathione content (39-44%) with a concomitant increase in lipid peroxidation (254-492%). Animals treated with RFFO/TPA and RFFE/TPA led a significant decrease in catalase (43-69%) and superoxide dismutase (20-31%) activities while glutathione reductase activity was found to be diminished (23-51%) in RFFO, RFFO/TPA, DMBA/RFFO, and RFFE/TPA treated groups. These results suggest that RFFE possess skin tumor initiating activity and that it may have weak promoting activity as well, which may involve free radicals.
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PMID:Assessment of carcinogenic potential of repeated fish fried oil in mice. 1668 49