logoAuthors: Goldstone, J.V., A.G. McArthur, A. Kubota, J. Zanette, T. Parente, M. Jönsson, D.R. Nelson, & J.J. Stegeman

BMC Genomics 2010, 11: 643.

Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development. Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human CYPs that are involved in endogenous functions including synthesis or inactivation of regulatory molecules. The high degree of sequence similarity suggests conservation of enzyme activities for these CYPs, confirmed in reports for some steroidogenic enzymes (e.g. CYP19, aromatase; CYP11A, P450scc; CYP17, steroid 17a-hydroxylase), and the CYP26 retinoic acid hydroxylases. Complexity is much greater in gene families 1, 2, and 3, which include CYPs prominent in metabolism of drugs and pollutants, as well as of endogenous substrates. There are orthologous relationships for some CYP1 s and some CYP3 s between zebrafish and human. In contrast, zebrafish have 47 CYP2 genes, compared to 16 in human, with only two (CYP2R1 and CYP2U1) recognized as orthologous based on sequence. Analysis of shared synteny identified CYP2 gene clusters evolutionarily related to mammalian CYP2 s, as well as unique clusters. Transcript profiling by microarray and quantitative PCR revealed that the majority of zebrafish CYP genes are expressed in embryos, with waves of expression of different sets of genes over the course of development. Transcripts of some CYP occur also in oocytes. The results provide a foundation for the use of zebrafish as a model in toxicological, pharmacological and chemical disease research.

DSC03269 copyIn 2006, Dr. McArthur left academia to act as a consultant in computational biology and bioinformatics for researchers in academia and government. With researchers at the Woods Hole Oceanographic Institution (Woods Hole, MA), McMaster University (Hamilton, Canada), and the University of Alabama (Tuscaloosa, AL), he performed research in environmental toxicology, with emphasis on microarray and genomic investigation of the molecular response of adult and developing zebrafish to metal (e.g. metal stress transcription factor MTF-1), organic (e.g. tBHQ, TCDD), and pharmaceutical (acetaminophen, gemfibrozil, carbamazapine and venlafaxine) pollutants. These efforts have recently been expanded to include both computational and ChIP-Seq investigation of the involved regulatory mechanisms. Another major research area was in the construction of the Comprehensive Antibiotic Resistance Database with a consortium of academic and government researchers in Canada and the United Kingdom, based at McMaster University. This project involves sequencing and assembly of novel bacterial pathogen genomes using both 454 and Illumina technologies, and subsequent annotation of possible antibiotic resistance genes and mechanisms, with implications for clinical treatment. Lastly, additional efforts focussed on natural resources management, with development of algorithms for wildlife population genomics analysis.