You are hereNews

News


Preparedness and response to chemical and biological threats: the role of exposure science.

Paul J. Lioy, Ph.D. - Mon, 02/19/2018 - 03:00

Related Articles Preparedness and response to chemical and biological threats: the role of exposure science. Ann N Y Acad Sci. 2016 Aug;1378(1):108-117 Authors: Lioy PJ, Laskin JD, Georgopoulos PG Abstract There are multiple components to emergency preparedness and the response to chemical and biological threat agents. The 5Rs framework (rescue, reentry, recovery, restoration, and rehabitation) outlines opportunities to apply exposure science in emergency events. Exposure science provides guidance and refined tools for characterizing, assessing, and reducing risks from catastrophic events, such as the release of hazardous airborne chemicals or biological agents. Important challenges to be met include deployment of assets, including medications, before and after an emergency response situation. Assessment of past studies demonstrates the value of integrating exposure science methods into risk analysis and the management of catastrophic events. PMID: 27479653 [PubMed - indexed for MEDLINE]

Categories: Publications from UCDPER Members

Selective Targeting of Heme Protein in Cytochrome P450 and Nitric Oxide Synthase by Diphenyleneiodonium.

Jeffrey D. Laskin, Ph.D. - Mon, 02/19/2018 - 03:00

Related Articles Selective Targeting of Heme Protein in Cytochrome P450 and Nitric Oxide Synthase by Diphenyleneiodonium. Toxicol Sci. 2016 May;151(1):150-9 Authors: Szilagyi JT, Mishin V, Heck DE, Jan YH, Aleksunes LM, Richardson JR, Heindel ND, Laskin DL, Laskin JD Abstract Cytochrome P450 (CYP) enzymes mediate mixed-function oxidation reactions important in drug metabolism. The aromatic heterocyclic cation, diphenyleneiodonium (DPI), binds flavin in cytochrome P450 reductase and inhibits CYP-mediated activity. DPI also inhibits CYP by directly interacting with heme. Herein, we report that DPI effectively inhibits a number of CYP-related monooxygenase reactions including NADPH oxidase, a microsomal enzyme activity that generates hydrogen peroxide in the absence of metabolizing substrates. Inhibition of monooxygenase by DPI was time and concentration dependent with IC50's ranging from 0.06 to 1.9 μM. Higher (4.6-23.9 μM), but not lower (0.06-1.9 μM), concentrations of DPI inhibited electron flow via cytochrome P450 reductase, as measured by its ability to reduce cytochrome c and mediate quinone redox cycling. Similar results were observed with inducible nitric oxide synthase (iNOS), an enzyme containing a C-terminal reductase domain homologous to cytochrome P450 reductase that mediates reduction of cytochrome c, and an N-terminal heme-thiolate oxygenase domain mediating nitric oxide production. Significantly greater concentrations of DPI were required to inhibit cytochrome c reduction by iNOS (IC50 = 3.5 µM) than nitric oxide production (IC50 = 0.16 µM). Difference spectra of liver microsomes, recombinant CYPs, and iNOS demonstrated that DPI altered heme-carbon monoxide interactions. In the presence of NADPH, DPI treatment of microsomes and iNOS yielded a type II spectral shift. These data indicate that DPI interacts with both flavin and heme in CYPs and iNOS. Increased sensitivity for inhibition of CYP-mediated metabolism and nitric oxide production by iNOS indicates that DPI targets heme moieties within the enzymes. PMID: 26880746 [PubMed - indexed for MEDLINE]

Categories: Publications from UCDPER Members