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Molecularkinetic characterization of the transport and the distribution of the pro-carcinogene Benzo[a]pyrene in vitro and in vivo ? new kinetic data for risk assessment
Project
Project code: BfR-LMS-08-1322-412
Contract period: 01.04.2009
- 31.12.2009
Purpose of research: Applied research
The interaction between the cytochrome P450-system, phase II xenobiotic-metabolizing en-zymes (XMEs) such as glutathione-S-transferases, UDP-glucuronosyl transferases and sul-fotransferases, and ABC-transport proteins is an important part of the mucosa of the small intestine acting as a potential biochemical barrier for nutritional- and eco-toxicological rele-vant compounds.Intestinal resorption of cancerogenic contaminants of food such as the polycyclic aromatic hydrocarbon (PAHs) benzo[a]pyrene (B[a]P) is affected by the interaction of CYP1A1/CYP1B1, phase II XMEs and ABC-transport proteins. It was shown that excretion of the B[a]P phase II metabolites including B[a]P-glucuronides and B[a]P-sulfates is medi-ated by breast cancer resistance protein (BCRP) (Ebert et al., 2005).In the project we here apply for the mechanism of detoxification of the ultimate carcino-genic phase I B[a]P metabolite anti-B[a]P-7,8-diol-9,10-epoxide (BPDE) will be studied. Formation of glutathione conjugates mediated by glutathione-S-transferases (GSTs) as well as the excretion of these conjugates will be analysed. Our studies will focus on the identification of transport proteins that are involved in GSH conjugate excretion. Prelimi-nary in vitro studies demonstrated that GSH conjugates of BPDE are primarily transported across the basolateral side of a polarized Caco-2 monolayer indicating that the apical ex-pressed BCRP is not involved in this export. Instead, the class of multidrug resistance as-soziated proteins (MRPs) may be responsible for BPDE excretion. In vivo studies by Srivastava et al. (2002) also indicate that MRPs are involved in BPDE transport processes. Therefore, the double MRP2/3 knock out mouse will be employed to analyse the influence of MRP2 and MRP3 in the distribution of the metabolites of B[a]P.
Section overview
Subjects
- Biotechnology
