Cytochromes P450 (CYPs), including CYPs 1A1 and lA2, are of particular importance in the metabolism and bioactivation of toxic xenobiotics, including environmental pollutants such as PCBs and TCDDs. The toxicity of such planar halogenated aromatic hydrocarbons (pHAHs) is in part mediated by the CYP-dependent production of reactive oxygen species (ROS). The quantitative dose-related linkages of pHAH -induced uncoupling of CYP1As to produce reactive oxygen have not been investigated in a coherent manner with regard to species and pHAH.
The specific aims are to determine quantitative pHAH-mediated linkages between uncoupling of CYP1As and ROS production in vitro and in cell lines for a consistent set of human and model organism CYP1 As, including both mice and zebrafish. TCDD has been shown to also increase the mitochondrial production of ROS. The relative balance of TCDD-dependent ROS production between mitochondria and CYP1As located in the endoplasmic reticulum is critical for evaluating the contributions of these two mechanisms to the overall production of ROS within a cell. Determination of the relative importance of CYPIA-mediated ROS stress versus mitochondrial production of ROS will be accomplished by localization of ROS production using confocal microscopy of fluorescent reactive oxygen probes. The mechanisms of CYP1A inactivation as a result of uncoupling will be investigating by determining the modification of the heme moiety and active site amino acid residues using HPLC and MALDI-ToF. Recently identified AhR-agonistic persistent pollutants, such as polybrominated diphenyl ethers will also be investigated.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Humble, Michael C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Woods Hole Oceanographic Institution
Other Domestic Higher Education
Woods Hole
United States
Zip Code
Nelson, David R; Goldstone, Jared V; Stegeman, John J (2013) The cytochrome P450 genesis locus: the origin and evolution of animal cytochrome P450s. Philos Trans R Soc Lond B Biol Sci 368:20120474
Stacke Ferreira, Roger; Monserrat, José Maria; Ribas Ferreira, Josencler Luís et al. (2012) Biomarkers of organic contamination in the South American fish Poecilia vivipara and Jenynsia multidentata. J Toxicol Environ Health A 75:1023-34
Goldstone, J V; Jönsson, M E; Behrendt, L et al. (2009) Cytochrome P450 1D1: a novel CYP1A-related gene that is not transcriptionally activated by PCB126 or TCDD. Arch Biochem Biophys 482:7-16
Jonsson, Maria E; Orrego, Rodrigo; Woodin, Bruce R et al. (2007) Basal and 3,3',4,4',5-pentachlorobiphenyl-induced expression of cytochrome P450 1A, 1B and 1C genes in zebrafish. Toxicol Appl Pharmacol 221:29-41
Goldstone, Jared V; Goldstone, Heather M H; Morrison, Ann M et al. (2007) Cytochrome P450 1 genes in early deuterostomes (tunicates and sea urchins) and vertebrates (chicken and frog): origin and diversification of the CYP1 gene family. Mol Biol Evol 24:2619-31
Prasad, Jahnavi C; Goldstone, Jared V; Camacho, Carlos J et al. (2007) Ensemble modeling of substrate binding to cytochromes P450: analysis of catalytic differences between CYP1A orthologs. Biochemistry 46:2640-54
Verslycke, Tim; Goldstone, Jared V; Stegeman, John J (2006) Isolation and phylogeny of novel cytochrome P450 genes from tunicates (Ciona spp.): a CYP3 line in early deuterostomes? Mol Phylogenet Evol 40:760-71
Goldstone, J V; Hamdoun, A; Cole, B J et al. (2006) The chemical defensome: environmental sensing and response genes in the Strongylocentrotus purpuratus genome. Dev Biol 300:366-84
Godard, Celine A J; Goldstone, Jared V; Said, Maya R et al. (2005) The new vertebrate CYP1C family: cloning of new subfamily members and phylogenetic analysis. Biochem Biophys Res Commun 331:1016-24