INDUCTION OF CARCINOGEN BINDING PROTEINS

描述（改编自申请人摘要）：持久

DESCRIPTION (Adapted from applicant's abstract): Persistent organochlorines (OCs) and polycyclic aromatic hydrocarbons (PAHs) are widespread chemical carcinogens which frequently co-occur in contaminated aquatic environments. Increased incidence of tumors and accumulation of carcinogen residues in feral fish inhabiting such sites presents a public health risk which is difficult to assess. This proposal focuses on increasing the understanding of hepatic uptake and intracellular transport of OCs and a genotoxic PAH in rainbow trout liver. Comparative studies using the rat are also proposed. The applicant hypothesizes that OC exposure induces proteins which bind and perhaps transport carcinogens within the hepatocyte. Stimulation of intracellular binding and processing of carcinogens by such induction relates to health risks in at least three ways. (1) These proteins likely play a key role in bioaccumulation of OCs and PAHs by fish which can presumably result in trophic transfer of these materials to humans. Traditional explanations for uptake of these agents by fish focused upon lipid partitioning. Improved understanding of the mechanistic basis for disposition of lipophilic carcinogens in fish is important for the development of adequate bioaccumulation models. (2) The role of environmental OCs and PAHs in tumor incidence in feral fish can be better assessed as mechanisms of interaction are defined. The applicant proposes rainbow trout tumor studies which will examine carcinogenity of OCs, their influence on initiation of PAH-induced cancer, and their activity in romotion/progression of PAH-induced cancer. Results of these tumor studies will be interpreted in light of what we learn about OC-induced carcinogen binding proteins. (3) The rainbow trout model is valuable for basic research on chemical carcinogenesis. The validity of the extrapolation of information on fish carcinogen binding proteins to human health will be directly assessed by comparative studies in the rat. An important attribute of the rainbow trout for studying carcinogen binding/transport proteins is the potential to induce these proteins without inducing the cytochrome P450 system. This provides an opportunity to study the tumorigenicity and biochemical toxicology of carcinogens in a system where binding and/or transport, rather than biotransformation, is preferentially modulated.