Title: Environmentally persistent free radical-containing particulate matter competitively inhibits metabolism by cytochrome P450 1A2.
Authors: Reed, James R; dela Cruz, Albert Leo N; Lomnicki, Slawo M; Backes, Wayne L
Published In Toxicol Appl Pharmacol, (2015 Dec 01)
Abstract: Combustion processes generate different types of particulate matter (PM) that can have deleterious effects on the pulmonary and cardiovascular systems. Environmentally persistent free radicals (EPFRs) represent a type of particulate matter that is generated after combustion of environmental wastes in the presence of redox-active metals and aromatic hydrocarbons. Cytochromes P450 (P450/CYP) are membrane-bound enzymes that are essential for the phase I metabolism of most lipophilic xenobiotics. The EPFR formed by chemisorption of 2-monochlorophenol to silica containing 5% copper oxide (MCP230) has been shown to generally inhibit the activities of different forms of P450s without affecting those of cytochrome P450 reductase and heme oxygenase-1. The mechanism of inhibition of rat liver microsomal CYP2D2 and purified rabbit CYP2B4 by MCP230 has been shown previously to be noncompetitive with respect to substrate. In this study, MCP230 was shown to competitively inhibit metabolism of 7-benzyl-4-trifluoromethylcoumarin and 7-ethoxyresorufin by the purified, reconstituted rabbit CYP1A2. MCP230 is at least 5- and 50-fold more potent as an inhibitor of CYP1A2 than silica containing 5% copper oxide and silica, respectively. Thus, even though PM generally inhibit multiple forms of P450, PM interacts differently with the forms of P450 resulting in different mechanisms of inhibition. P450s function as oligomeric complexes within the membrane. We also determined the mechanism by which PM inhibited metabolism by the mixed CYP1A2-CYP2B4 complex and found that the mechanism was purely competitive suggesting that the CYP2B4 is dramatically inhibited when bound to CYP1A2.
PubMed ID: 26423927
MeSH Terms: Animals; Aryl Hydrocarbon Hydroxylases/metabolism; Binding Sites; Binding, Competitive; Catalytic Domain; Coumarins/metabolism; Cytochrome P-450 CYP1A2 Inhibitors/metabolism; Cytochrome P-450 CYP1A2 Inhibitors/toxicity*; Cytochrome P-450 CYP1A2/metabolism*; Cytochrome P450 Family 2; Dose-Response Relationship, Drug; Environmental Pollutants/metabolism; Environmental Pollutants/toxicity*; Free Radicals/metabolism; Free Radicals/toxicity*; Liver/drug effects*; Liver/enzymology; Oxazines/metabolism; Particulate Matter/metabolism; Particulate Matter/toxicity*; Protein Binding; Rabbits; Substrate Specificity