AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1

Bibliographic Details
Main Author:	CLAY, COREY DAVIS
Language:	English
Published:	University of Cincinnati / OhioLINK 2003
Subjects:	AHR AHR gene battery PCB PBB microsome
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1061220136

id	ndltd-OhioLink-oai-etd.ohiolink.edu-ucin1061220136
record_format	oai_dc
spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-ucin10612201362021-08-03T06:09:17Z AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1 CLAY, COREY DAVIS AHR AHR gene battery PCB PBB microsome 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmentally persistent compound that causes cancer and toxicity in multiple organ systems. Because of its potency, other structurally similar hazardous toxicants are compared to TCDD if they act through the same toxicological mechanism. Coplanar polyhalogenated biphenyls (PHBs) have TCDD toxic equivalency (TEQ), whereas noncoplanar PHBs do not. The TEQ-associated toxicological mechanism involves an oxidative stress response, but the intracellular source of reactive oxygen species (ROS) is unconfirmed. The requirement for activation of the aromatic hydrocarbon receptor (AHR) is well established, however. The AHR is a cytosolic factor that is activated upon binding TCDD-like compounds. Activation results in translocation into the nucleus and transcription of the "AHR" gene battery. Phase I monooxygenase enzymes, cytochromes P4501A1 and P4501A2 (CYP1A1 and CYP1A2), are among "AHR" gene battery products. Enzymatic uncoupling of substrate hydroxylation from oxygen consumption generates ROS and might contribute to TEQ-associated toxicity. Various substrates, including TCDD and PHBs, are examined in this study for their ability to induce monooxygenase uncoupling in isolated microsomes containing or lacking AHR-controlled cytochromes P450. Microsomes were isolated from "wild-type" mice, "Cyp1a1 (-/-)" knockout mice and "Cyp1a2 (-/-)" knockout mice to examine relative CYP isoform-specific contributions to ROS generation. Results show increased uncoupling of CYP1A1 in the presence of highly halogenated, coplanar substrates only. Thus, CYP uncoupling likely contributes to TEQ-associated toxicity since previously identified TCDD-like PHBs are shown to cause CYP uncoupling rates comparable to TCDD-induced rates. Non-AHR-controlled CYP2E1 is identified as the predominant CYP isoform responsible for basal levels of ROS generation in the absence of substrates. Surprisingly, CYP1A2 is found to act in an anti-oxidant manner by attenuating ROS generation by both pro-oxidant CYP1A1 and CYP2E1. Evidence is shown that a direct electron flow between these CYP isoforms exists and that CYP1A2 diverts electrons to an unknown electron sink. In conclusion, this thesis implicates a role for CYP uncoupling in TEQ-associated toxicity and introduces both the concept of direct inter-CYP electron transfer and the concept that anti-oxidant CYPs protect against oxidative stress. 2003-09-02 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1061220136 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1061220136 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	AHR AHR gene battery PCB PBB microsome
spellingShingle	AHR AHR gene battery PCB PBB microsome CLAY, COREY DAVIS AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1
author	CLAY, COREY DAVIS
author_facet	CLAY, COREY DAVIS
author_sort	CLAY, COREY DAVIS
title	AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1
title_short	AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1
title_full	AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1
title_fullStr	AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1
title_full_unstemmed	AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1
title_sort	evaluation of tcdd and polyhalogenated biphenyl mediated reactive oxygen generation by cytochromes p4501a1, p4501a2 and p4502e1
publisher	University of Cincinnati / OhioLINK
publishDate	2003
url	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1061220136
work_keys_str_mv	AT claycoreydavis anevaluationoftcddandpolyhalogenatedbiphenylmediatedreactiveoxygengenerationbycytochromesp4501a1p4501a2andp4502e1 AT claycoreydavis evaluationoftcddandpolyhalogenatedbiphenylmediatedreactiveoxygengenerationbycytochromesp4501a1p4501a2andp4502e1
_version_	1719431812316397568

AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1

Similar Items