Cytochrome P450 Family 1 and 3 Function in Aquatic Species

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Cytochrome P450 enzymes (CYPs) are critical for the production and metabolism of important molecules such as hormones. CYPs are also critical for the metabolism of environmental contaminants. Genes in the CYP1 and CYP3 families mediate both xenobiotic and steroid metabolism. Despite their roles, we are only beginning to understand the regulation and function of CYP genes in aquatic species. Our lab has played an important role in the identification and study of CYPs in fish and aquatic annelids. Newly identified CYP1 and CYP3 family gene sequences in both groups suggest novel metabolic functions. To build on research previously completed in our laboratory, the major objectives of this research are to understand the regulation, expression and function of xenobiotic and steroid metabolizing genes in aquatic species. The hypothesis is that diversity in gene sequences predicts the acquisition of novel metabolic function in aquatic species. Using zebrafish as a model teleost species, we will examine CYP1D1 and CYP3C1-4. Function will be assessed by using expressed proteins in a high through put screening approach developed in our last NSERC Discovery. Work from others (CYP1D1) and in our last Discovery (CYP3C1-4) identified the tissue and developmental expression patterns of these genes and suggested the regulatory pathways that may control gene expression. Using pharmacological tools, we will determine the regulation of CYP1D1 and CYP3C1-4 genes in zebrafish. In our last Discovery, our annotation of CYP genes in the genome of the annelid, Capitella telata, identified several CYP1 and CYP3 related genes, two of which have been implicated in xenobiotic metabolism. This aquatic annelid has the capacity to metabolize vertebrate CYP1 substrates, such as polycyclic aromatic hydrocarbons, which are common environmental contaminants. This ability has been linked to the dominance of Capitella in highly contaminated environments and suggests resistance to toxic chemicals. Our prior studies have identified candidates genes for steroid and xenobiotic metabolism and in this proposal we will assess the capacity of Capitella for these functions. Since CYP1 and CYP3 families play such an important role in both steroid and xenobiotic metabolism, we propose to focus on understanding the regulation and function of novel CYP1 and CYP3 genes in aquatic species. These data will determine if novelty in CYP gene sequences has led to novel metabolic capacity that allows these species to withstand contaminated environments. We can apply this knowledge to understand the capacity of a species for xenobiotic metabolism, to understand the relevance of CYP genes for toxicology, and to understand the evolution of detoxification systems.**