Metabolism of 3,5,3′,5′-tetrachlorobiphenyl by rat liver microsomes and purified P4501A1

Koga, Nobuyuki; Nishimura, N; Kuroki, Hiroaki; Masuda, Yoshito; Yoshimura, Hidetoshi

doi:10.3109/00498259409043277

Cited by 5 publications

(2 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2,4,39,49-, 3,4,39,49-, and 3,5,39,59-TCB (Fig. 1) and the metabolites 3-hydroxy-2,5,39,49-TCB, a mixture of 3-hydroxy-and 4-hydroxy-2,5,39,49-TCB, 5-hydroxy-2,4,39,49-TCB, 4-hydroxy-2,3,39,49-TCB (a metabolite of 2,4,39,49-TCB), and 4-hydroxy-3,5,39,59-TCB were obtained from the sources described previously (Koga et al, 1989(Koga et al, , 1992(Koga et al, , 1994.…”

Section: Methodsmentioning

confidence: 99%

Roles of Human CYP2A6 and Monkey CYP2A24 and 2A26 Cytochrome P450 Enzymes in the Oxidation of 2,5,2′,5′-Tetrachlorobiphenyl

Shimada

Kakimoto

Takenaka

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

2,5,2',5'-Tetrachlorobiphenyl (TCB) induced type I binding spectra with cytochrome P450 (P450) 2A6 and 2A13, with K values of 9.4 and 0.51 µM, respectively. However, CYP2A6 oxidized 2,5,2',5'-TCB to form 4-hydroxylated products at a much higher rate (∼1.0 minute) than CYP2A13 (∼0.02 minute) based on analysis by liquid chromatography-tandem mass spectrometry. Formation of 4-hydroxy-2,5,2',5'-TCB by CYP2A6 was greater than that of 3-hydroxy-2,5,2',5'-TCB and three other hydroxylated products. Several human P450 enzymes, including CYP1A1, 1A2, 1B1, 2B6, 2D6, 2E1, 2C9, and 3A4, did not show any detectable activities in oxidizing 2,5,2',5'-TCB. Cynomolgus monkey CYP2A24, which shows 95% amino acid identity to human CYP2A6, catalyzed 4-hydroxylation of 2,5,2',5'-TCB at a higher rate (∼0.3 minute) than CYP2A26 (93% identity to CYP2A6, ∼0.13 minute) and CYP2A23 (94% identity to CYP2A13, ∼0.008 minute). None of these human and monkey CYP2A enzymes were catalytically active in oxidizing other TCB congeners, such as 2,4,3',4'-, 3,4,3',4'-, and 3,5,3',5'-TCB. Molecular docking analysis suggested that there are different orientations of interaction of 2,5,2',5'-TCB with the active sites (over the heme) of human and monkey CYP2A enzymes, and that ligand interaction energies (U values) of bound protein-ligand complexes show structural relationships of interaction of TCBs and other ligands with active sites of CYP2A enzymes. Catalytic differences in human and monkey CYP2A enzymes in the oxidation of 2,5,2',5'-TCB are suggested to be due to amino acid changes at substrate recognition sites, i.e., V110L, I209S, I300F, V365M, S369G, and R372H, based on the comparison of primary sequences.

show abstract

Section: Methodsmentioning

confidence: 99%

Roles of Human CYP2A6 and Monkey CYP2A24 and 2A26 Cytochrome P450 Enzymes in the Oxidation of 2,5,2′,5′-Tetrachlorobiphenyl

Shimada

Kakimoto

Takenaka

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…Following in vivo administration, PCBs are converted by cytochrome P450 (CYP) in the liver to hydroxy-PCB (HO-PCB), which is one of its active metabolites , . 4-Hydroxylation of PCB proceeds via 3,4-epoxide because reduced glutathione completely inhibits the formation of the hydroxylated metabolite . Both PCBs and HO-PCBs have weak estrogenic and thyroid hormonal activities, and these effects are thought to be mediated through the estrogen and thyroid hormone receptors, respectively.…”

Section: Introductionmentioning

confidence: 99%

Hydroxylated Polychlorinated Biphenyls (PCBs) Interact with Protein Disulfide Isomerase and Inhibit Its Activity

Okada

Hashimoto

Funae

et al. 2009

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Protein disulfide isomerase (PDI) is a catalyst of isomerization of substrate protein intra- and extra-molecular disulfide bridges and also has 3,3',5-triiodo-l-thyronine (T(3))-binding activity and molecular chaperone-like activity. We previously found that halogenated derivatives of bisphenol A as well as bisphenol A itself bind to PDI and thereby suppress the oxidative refolding of reduced RNaseA by PDI. Polychlorinated biphenyls (PCBs) are environmental endocrine-disrupting chemicals that cause various abnormalities in many organs such as the central nervous system. PCBs are metabolized to hydroxylated compounds (HO-PCBs) in humans and other animals, and HO-PCBs gain toxicity by metabolism. In the present study, 2',3,3',4',5'-pentachlorobiphenyl (penCB), 2',3,3',5,5',6'-hexachlorobiphenyl (hexCB), and their 4-hydroxylated metabolites (HO-penCB and HO-hexCB, respectively) were used to examine whether they interact with PDI and inhibit its activity. HO-penCB and HO-hexCB markedly inhibited the binding of T(3) to PDI. However, nonhydroxylated PCBs did not show any interaction with PDI. The effects of PCBs and HO-PCBs on PDI activity were also investigated using an RNaseA refolding assay. Both HO-PCBs inhibited the oxidative refolding of reduced RNaseA by PDI. We also assessed the effects of HO-PCBs and PCBs on the chaperone activity of PDI, which was measured by a thermal aggregation assay, and found that neither HO-PCBs nor PCBs have significant inhibitory or promoting effects. These findings suggest that the metabolites of PCBs have the potential to cause defective protein folding via PDI.

show abstract

Procedures for analysing phenolic metabolites of polychlorinated dibenzofurans, -dibenzo-p-dioxins and -biphenyls extracted from a microsomal assay: optimising solid-phase adsorption clean-up and derivatisation methods

Rozemeijer

Olie

Voogt

1997

Journal of Chromatography A

View full text Add to dashboard Cite

Metabolism of 3,5,3′,5′-tetrachlorobiphenyl by rat liver microsomes and purified P4501A1

Cited by 5 publications

References 24 publications

Roles of Human CYP2A6 and Monkey CYP2A24 and 2A26 Cytochrome P450 Enzymes in the Oxidation of 2,5,2′,5′-Tetrachlorobiphenyl

Roles of Human CYP2A6 and Monkey CYP2A24 and 2A26 Cytochrome P450 Enzymes in the Oxidation of 2,5,2′,5′-Tetrachlorobiphenyl

Hydroxylated Polychlorinated Biphenyls (PCBs) Interact with Protein Disulfide Isomerase and Inhibit Its Activity

Procedures for analysing phenolic metabolites of polychlorinated dibenzofurans, -dibenzo-p-dioxins and -biphenyls extracted from a microsomal assay: optimising solid-phase adsorption clean-up and derivatisation methods

Contact Info

Product

Resources

About