Uncoupling-mediated generation of reactive oxygen by halogenated aromatic hydrocarbons in mouse liver microsomes

Howard G. Shertzer; Corey D. Clay; Mary Beth Genter; Mark C. Chames; Scott N. Schneider; Greg G. Oakley; Daniel W. Nebert; Timothy P. Dalton

doi:10.1016/j.freeradbiomed.2003.11.014

Uncoupling-mediated generation of reactive oxygen by halogenated aromatic hydrocarbons in mouse liver microsomes

Howard G. Shertzer, Corey D. Clay, Mary Beth Genter, Mark C. Chames, Scott N. Schneider, Greg G. Oakley, Daniel W. Nebert, Timothy P. Dalton

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

Studying liver microsomes from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced or vehicle-treated (noninduced) mice, we evaluated the in vitro effects of added chemicals on the production of reactive oxygen due to substrate/P450-mediated uncoupling. The catalase-inhibited NADPH-dependent H₂O₂ production (luminol assay) was lower in induced than noninduced microsomes. The effects of adding chemicals (2.5 μM) in vitro could be divided into three categories: Group 1, highly halogenated and coplanar compounds that increased H₂O₂ production at least 5-fold in induced, but not in noninduced, microsomes; Group 2, non-coplanar halogenated biphenyls that did not affect H₂O ₂ production; Group 3, minimally halogenated biphenyls and benzo[a]pyrene that decreased H₂O₂ production. Molar consumption of NADPH and O₂ and molar H₂O₂ production (o-dianisidine oxidation) revealed that Group 1 compounds mostly increased, Group 2 had no effect, and Group 3 decreased the H₂O ₂/O₂ and H₂O₂/NADPH ratios. Microsomal lipid peroxidation (thiobarbituric acid-reactive substances) was proportional to H₂O₂ production. Although TCDD induction decreased microsomal production of H₂O₂, addition of Group 1 compounds to TCDD-induced microsomes in vitro stimulated the second-electron reduction of cytochrome P450 and subsequent release of H ₂O₂ production. This pathway is likely to contribute to the oxidative stress response and associated toxicity produced by many of these environmental chemicals.

Original language	English (US)
Pages (from-to)	618-631
Number of pages	14
Journal	Free Radical Biology and Medicine
Volume	36
Issue number	5
DOIs	https://doi.org/10.1016/j.freeradbiomed.2003.11.014
State	Published - Mar 1 2004
Externally published	Yes

Keywords

Cytochrome P450
Free radicals
Hydrogen peroxide
Polyhalogenated aromatic hydrocarbons
Superoxide
Uncoupling

ASJC Scopus subject areas

Biochemistry
Physiology (medical)

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10.1016/j.freeradbiomed.2003.11.014

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@article{db80c8de6934446cb3c224970ee6a3c8,

title = "Uncoupling-mediated generation of reactive oxygen by halogenated aromatic hydrocarbons in mouse liver microsomes",

abstract = "Studying liver microsomes from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced or vehicle-treated (noninduced) mice, we evaluated the in vitro effects of added chemicals on the production of reactive oxygen due to substrate/P450-mediated uncoupling. The catalase-inhibited NADPH-dependent H2O2 production (luminol assay) was lower in induced than noninduced microsomes. The effects of adding chemicals (2.5 μM) in vitro could be divided into three categories: Group 1, highly halogenated and coplanar compounds that increased H2O2 production at least 5-fold in induced, but not in noninduced, microsomes; Group 2, non-coplanar halogenated biphenyls that did not affect H2O 2 production; Group 3, minimally halogenated biphenyls and benzo[a]pyrene that decreased H2O2 production. Molar consumption of NADPH and O2 and molar H2O2 production (o-dianisidine oxidation) revealed that Group 1 compounds mostly increased, Group 2 had no effect, and Group 3 decreased the H2O 2/O2 and H2O2/NADPH ratios. Microsomal lipid peroxidation (thiobarbituric acid-reactive substances) was proportional to H2O2 production. Although TCDD induction decreased microsomal production of H2O2, addition of Group 1 compounds to TCDD-induced microsomes in vitro stimulated the second-electron reduction of cytochrome P450 and subsequent release of H 2O2 production. This pathway is likely to contribute to the oxidative stress response and associated toxicity produced by many of these environmental chemicals.",

keywords = "Cytochrome P450, Free radicals, Hydrogen peroxide, Polyhalogenated aromatic hydrocarbons, Superoxide, Uncoupling",

author = "Shertzer, {Howard G.} and Clay, {Corey D.} and Genter, {Mary Beth} and Chames, {Mark C.} and Schneider, {Scott N.} and Oakley, {Greg G.} and Nebert, {Daniel W.} and Dalton, {Timothy P.}",

note = "Funding Information: We thank our colleagues for a careful reading of this manuscript. The work was funded, in part, by NIH Grants R01 ES10133, R01 ES06321, R01 ES08147, T32 ES07250, and P30 ES06096.",

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doi = "10.1016/j.freeradbiomed.2003.11.014",

language = "English (US)",

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journal = "Free Radical Biology and Medicine",

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T1 - Uncoupling-mediated generation of reactive oxygen by halogenated aromatic hydrocarbons in mouse liver microsomes

AU - Shertzer, Howard G.

AU - Clay, Corey D.

AU - Genter, Mary Beth

AU - Chames, Mark C.

AU - Schneider, Scott N.

AU - Oakley, Greg G.

AU - Nebert, Daniel W.

AU - Dalton, Timothy P.

N1 - Funding Information: We thank our colleagues for a careful reading of this manuscript. The work was funded, in part, by NIH Grants R01 ES10133, R01 ES06321, R01 ES08147, T32 ES07250, and P30 ES06096.

PY - 2004/3/1

Y1 - 2004/3/1

N2 - Studying liver microsomes from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced or vehicle-treated (noninduced) mice, we evaluated the in vitro effects of added chemicals on the production of reactive oxygen due to substrate/P450-mediated uncoupling. The catalase-inhibited NADPH-dependent H2O2 production (luminol assay) was lower in induced than noninduced microsomes. The effects of adding chemicals (2.5 μM) in vitro could be divided into three categories: Group 1, highly halogenated and coplanar compounds that increased H2O2 production at least 5-fold in induced, but not in noninduced, microsomes; Group 2, non-coplanar halogenated biphenyls that did not affect H2O 2 production; Group 3, minimally halogenated biphenyls and benzo[a]pyrene that decreased H2O2 production. Molar consumption of NADPH and O2 and molar H2O2 production (o-dianisidine oxidation) revealed that Group 1 compounds mostly increased, Group 2 had no effect, and Group 3 decreased the H2O 2/O2 and H2O2/NADPH ratios. Microsomal lipid peroxidation (thiobarbituric acid-reactive substances) was proportional to H2O2 production. Although TCDD induction decreased microsomal production of H2O2, addition of Group 1 compounds to TCDD-induced microsomes in vitro stimulated the second-electron reduction of cytochrome P450 and subsequent release of H 2O2 production. This pathway is likely to contribute to the oxidative stress response and associated toxicity produced by many of these environmental chemicals.

AB - Studying liver microsomes from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced or vehicle-treated (noninduced) mice, we evaluated the in vitro effects of added chemicals on the production of reactive oxygen due to substrate/P450-mediated uncoupling. The catalase-inhibited NADPH-dependent H2O2 production (luminol assay) was lower in induced than noninduced microsomes. The effects of adding chemicals (2.5 μM) in vitro could be divided into three categories: Group 1, highly halogenated and coplanar compounds that increased H2O2 production at least 5-fold in induced, but not in noninduced, microsomes; Group 2, non-coplanar halogenated biphenyls that did not affect H2O 2 production; Group 3, minimally halogenated biphenyls and benzo[a]pyrene that decreased H2O2 production. Molar consumption of NADPH and O2 and molar H2O2 production (o-dianisidine oxidation) revealed that Group 1 compounds mostly increased, Group 2 had no effect, and Group 3 decreased the H2O 2/O2 and H2O2/NADPH ratios. Microsomal lipid peroxidation (thiobarbituric acid-reactive substances) was proportional to H2O2 production. Although TCDD induction decreased microsomal production of H2O2, addition of Group 1 compounds to TCDD-induced microsomes in vitro stimulated the second-electron reduction of cytochrome P450 and subsequent release of H 2O2 production. This pathway is likely to contribute to the oxidative stress response and associated toxicity produced by many of these environmental chemicals.

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KW - Free radicals

KW - Hydrogen peroxide

KW - Polyhalogenated aromatic hydrocarbons

KW - Superoxide

KW - Uncoupling

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Uncoupling-mediated generation of reactive oxygen by halogenated aromatic hydrocarbons in mouse liver microsomes

Abstract

Keywords

ASJC Scopus subject areas

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