Studies on the structure-activity relationships for the metabolism of polybrominated biphenyls by rat liver microsomes

Mills, Richard A.; Millis, Cynthia D.; Dannan, Ghazi A.; Guengerich, F. Peter; Aust, Steven D.

doi:10.1016/0041-008x(85)90309-6

Cited by 74 publications

(40 citation statements)

References 28 publications

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“…nonortho and some mono-ortho substituted PCBs and 2,3,7, and polycyclic aromatic hydrocarbons (PAHs). In rat liver, CYP1A1 is important in phase I oxidative metabolism of PCB congeners with chlorine substituents at one or both para positions, and with adjacent non-halogenated ortho and meta carbons on at least one ring (Kaminsky et al, 1981;Mills et al, 1985). CYP1A1 metabolism of these parent PCB congeners generates hydroxylated metabolites (OH-PCBs) (Kaminsky et al, 1981;Mills et al, 1985;.…”

Section: Resultsmentioning

confidence: 99%

“…In rat liver, CYP1A1 is important in phase I oxidative metabolism of PCB congeners with chlorine substituents at one or both para positions, and with adjacent non-halogenated ortho and meta carbons on at least one ring (Kaminsky et al, 1981;Mills et al, 1985). CYP1A1 metabolism of these parent PCB congeners generates hydroxylated metabolites (OH-PCBs) (Kaminsky et al, 1981;Mills et al, 1985;. In vitro biotransformation studies using beluga whale liver microsomes have demonstrated the production of OH-PCBs in cetaceans by CYP1A1 .…”

Section: Resultsmentioning

confidence: 99%

“…Lower chlorinated PCB congeners with chlorine substituents at one or both para positions, and with vicinal hydrogens at the ortho-meta positions are oxidized by CYP1A1 (Ishida et al, 1991;Kaminsky et al, 1981;Mills et al, 1985;Shimada and Sawabe, 1983). Therefore, the lower chlorinated OH-PCB congeners that were significantly higher in CHS dolphins (i.e.…”

Section: Relationship Between Cyp1a1 Expression and Oh-pcbsmentioning

confidence: 99%

“…In rat liver, CYP1A is important in phase I oxidative metabolism of PCB congeners with chlorine substituents at one or both para positions, and with adjacent non-halogenated ortho and meta carbons on at least one ring (Kaminsky et al, 1981;Mills et al, 1985). CYP2B is important in phase I oxidative metabolism of PCB congeners that have two ortho-chlorines and meta-, para-vicinal hydrogens.…”

Section: Induction Of Xenobiotic Metabolizing Enzymes and Formation Omentioning

confidence: 99%

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Approaches for assessing the presence and impact of thyroid hormone disrupting chemicals in delphinid cetaceans

Montie¹

2006

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Cetacean blubber is a primary site for lipid storage, which the animal utilizes during periods of energetic stress. It is important to understand how the blubber responds to factors such as ontogeny, water temperature, reproductive status, and nutritional state because blubber is also the primary bioaccumulation site for persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs). During periods of lipid mobilization such as lactation, PCBs from the blubber are mobilized into the circulatory system and may cause toxic effects. One particular toxic mechanism may include the induction of cytochrome P450 enzymes in the integument and liver, which could enhance the biotransformation of PCBs to hydroxylated metabolites (OH-PCBs). OH-PCBs may then interfere with thyroid hormone dependent neurodevelopment. The goals of these studies were to investigate the relationships between lipid dynamics and PCB effects and to devise a quantitative approach to assess neurodevelopment in delphinid cetaceans. Blubber morphology, cytochrome P450 1A1 (CYP1A1) expression in the skin-blubber biopsy, blubber and plasma PCBs, and plasma OH-PCBs were assessed in bottlenose dolphins (Tursiops truncatus). In addition, magnetic resonance (MR) images of the postmortem brain in situ were obtained from Atlantic white-sided dolphin (Lagenorhynchus acutus) specimens.These results showed that: 1) Factors such as ontogeny, water temperature, and reproductive status affected blubber morphology in bottlenose dolphins. In response to warmer water, the lipid content of the blubber decreased and this appeared to involve loss of lipids from adipocytes in the middle blubber layer. Similar to the effects of starvation on blubber morphology, lactation decreased adipocyte size predominantly in the deeper blubber, 2) CYP1A1 levels in the deep blubber were significantly related to the total plasma TEQ 98 concentrations, adipocyte shrinkage, and plasma OH-PCB levels, 3) Through in situ MR imaging of stranded, Atlantic white-sided dolphin specimens, the size of brain structures that depend on thyroid hormones for maturation could be measured accurately. Future studies can use this technique, coupled with chemical analysis of brain regions, to determine if thyroid hormone disrupting chemicals in delphinid cetaceans are associated with changes in the size of brain structures.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Relationship Between Cyp1a1 Expression and Oh-pcbsmentioning

confidence: 99%

Section: Induction Of Xenobiotic Metabolizing Enzymes and Formation Omentioning

confidence: 99%

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Approaches for assessing the presence and impact of thyroid hormone disrupting chemicals in delphinid cetaceans

Montie¹

2006

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“…In rat liver, hydrocarbon-inducible CYP1A forms metabolize congeners with halogenated substituents at one or both para positions, and with adjacent unsubstituted ortho-meta carbons, while phenobarbital-inducible CYP2B forms (CYP2B 1, CYP2B2) metabolize congeners with adjacent, unsubstituted meta-para positions Kennedy et al, 1981;Shimada and Sawabe, 1983;Mills et al, 1985;Ishida et al, 1991). In addition, it was observed that PCB congeners with two or more ortho substituents are more rapidly metabolized by rat CYP2B than by CYP A, while congeners lacking ortho substituents are more rapidly metabolized by rat CYP1A than by CYP2B.…”

Section: Polychlorinated Biphenyls: Distribution Toxicity Metabolismmentioning

confidence: 99%

Tetrachlorobiphenyl metabolism, toxicity, and regulation of cytochrome P50 expression in a marine teleost fish

White¹

1994

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The effects of 3,3',4,4'-tetrachlorobiphenyl (TCB) were examined in the marine fish scup (Stenotomus chrysops), focusing on the interactions between TCB and the CYP1A1 enzyme system. A low TCB dose (0.1 mg/kg) elicited strong and sustained induction of hepatic CYPlA1 mRNA, protein content, and catalytic activity. A high TCB dose (5.0 mg/kg) elicited similar, strong induction of hepatic CYPlA1 mRNA, but not of CYPlA1 protein content or catalytic activity. This post-transcriptional "suppression" at the high TCB dose was specific for CYPlA1, and was not seen with other hepatic enzymes. In vitro studies indicate that hepatic microsomal CYP A1 is inactivated in the presence of TCB plus cofactor, likely due to the production of reactive oxygen species during TCB occupation of the active site. CYPlA1 inactivation by TCB in vitro may explain the TCBelicited suppression of CYPlA1 protein content in vivo.Both TCB doses elicited strong CYPlA1 induction in vascular endothelium of all organs, which was sustained for several weeks. Induction in intestinal epithelia was stronger at the high TCB dose, but induction in epithelia of liver, kidney, and gill were stronger at the low TCB dose. Both TCB doses caused proliferation of endoplasmic reticulum in liver, renal tubule necrosis, depletion of hematopoietic tissue in kidney, hyperplasia of gill epithelia, and increased number of melanomacrophage aggregates in spleen. The high dose induced tail fin erosion, affecting both epithelial and calcified bone tissue. Tissue alterations were more severe at the high TCB dose, and repair of lesions occurred by day 16 at the low dose. The high dose caused mortality of many individuals.The two TCB congeners 3,3',4,4'-TCB and 2,2',5,5'-TCB were each converted to aqueous-soluble metabolites by hepatic microsomes from scup, beluga whale, and pilot whale. Induction response, correlation analysis, and inhibition studies indicate that 3,3',4,4'-TCB is metabolized by scup CYP1Al, and 2,2',5,5'-TCB by the putative scup CYP2B. Correlation analysis and inhibition studies suggest that 3,3',4,4'-TCB is metabolized by cetacean CYP1A. Both cetacean species expressed microsomal proteins that are immunochemically related to mammalian CYP2B forms. Cytochrome P450 systems from both cetacean species are partially characterized here.

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Using Structural Information to Create Physiologically Based Pharmacokinetic Models for All Polychlorinated Biphenyls

Parham

Kohn

Matthews

et al. 1997

Toxicology and Applied Pharmacology

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Studies on the structure-activity relationships for the metabolism of polybrominated biphenyls by rat liver microsomes

Cited by 74 publications

References 28 publications

Approaches for assessing the presence and impact of thyroid hormone disrupting chemicals in delphinid cetaceans

Approaches for assessing the presence and impact of thyroid hormone disrupting chemicals in delphinid cetaceans

Tetrachlorobiphenyl metabolism, toxicity, and regulation of cytochrome P50 expression in a marine teleost fish

Using Structural Information to Create Physiologically Based Pharmacokinetic Models for All Polychlorinated Biphenyls

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