Skip navigation
Food Standards Agency
Friday 3 July 2009
Safer food better business banner
AZ-Directory
What's New
T01035: Signal transduction pathways involved in cell proliferation and motility induced by the food-derived carcinogen PhIP
Wednesday 24 March 2004
This research project investigates whether PhIP, or its metabolites, influence cell proliferation and cell growth.
Study Duration
: June 2003 to May 2005
Contractor
: Imperial College London
Background
This project investigated, the mechanisms of toxicity that give PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) the ability to induce tissue-specific cancer at the cellular level. Particular emphasis was focused on effects on cells of the breast.
This study follows up the results of a short study carried out by the Department of Health Toxicology Unit to which the FSA contributed. A summary is appended to the report and the full report is available on request.
Research Approach
Human breast epithelial cells will be used to examine the effect of PhIP treatment on MAP kinase signal transduction pathways and the functional consequences of the effects using Western blotting, kinase assays, motility assays and changes in transcriptional regulation.
Where possible, concentrations of PhIP used will be similar to those consumed by humans from a cooked meat meal.
Results and findings
The project devised a cell-based co-culture model to evaluate the effect of metabolically activated PhIP on breast cells.
-
Exposure to high concentrations of PhIP led to inhibition of breast cell growth and DNA damage that resulted in changes in the levels of key survival proteins
-
Exposure to low concentrations of PhIP induced cell proliferation in oestrogen receptor positive and negative breast cells. PhIP also induced malignant cell-like migration, although this effect was only seen in cells expressing the oestrogen receptor
-
These powerful biological effects appear to be controlled by specific signalling pathways and are likely determinants of PhIP’s highly selective tissue-specific cancer causing ability
-
In order to establish the importance of these effects in the aetiology of diet-associated cancer, these findings need to be confirmed in animal studies and ultimately in humans
Published papers
-
Lauber, S.N., Ali, S., Gooderham, N.J. (2004). The cooked food derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potent oestrogen: A mechanistic basis for its tissue specific carcinogenicity. Carcinogenesis, 25: 2509-2517
-
Creton, S., Zhu, H., Gooderham, N.J. (2005). A mechanistic basis for the role of cycle arrest in the genetic toxicology of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Toxicol Sci, 84: 335-343
-
Zhu, H. Smith, C., Ansah, C., Gooderham, N.J. (2005). Responses of genes involved in cell cycle control to diverse DNA damaging chemicals in human lung adenocarcinoma A549 cells. Cancer Cell Int, 5(28): 1-13
-
Lauber, S.N., and Gooderham, N.J. (2007). The cooked meat–derived genotoxic carcinogen 2-amino-3-methylimidazo[4,5-b]pyridine has potent hormone-like activity: Mechanistic support for a role in breast cancer; Cancer Res
67: (19): 9597 – 9602
-
Creton, S.K., Zhu, H. and Gooderham, N.J. (2007). The cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) stimulates cell proliferation and migration via activation of the ERK MAP kinase pathway. Cancer Res ;67 (23): 11455 - 11462
Related links
T01/T05/T09 Programme Review 2007
Find out what our other sites have to offer
Change Text Only Settings
Graphic version of this page