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

CLAY, COREY DAVIS
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1061220136

Abstract Details

2003, MS, University of Cincinnati, Medicine : Environmental Health Sciences.
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.
Dr. Howard Shertzer (Advisor)
101 p.
AHR; AHR gene battery; PCB; PBB; microsome

Recommended Citations

Citations

  • CLAY, C. D. (2003). AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1 [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1061220136

    APA Style (7th edition)

  • CLAY, COREY. AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1. 2003. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1061220136.

    MLA Style (8th edition)

  • CLAY, COREY. "AN EVALUATION OF TCDD AND POLYHALOGENATED BIPHENYL MEDIATED REACTIVE OXYGEN GENERATION BY CYTOCHROMES P4501A1, P4501A2 AND P4502E1." Master's thesis, University of Cincinnati, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1061220136

    Chicago Manual of Style (17th edition)

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© 2003, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.