Impact of phenanthrene co-administration on the toxicokinetics of benzo[a]pyrene in humans. UPLC-accelerator mass spectrometry following oral microdosing.

Autor: Maier MLV; Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA. Electronic address: monica.maier@oregonstate.edu., Siddens LK; Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA. Electronic address: beth.siddens@oregonstate.edu., Pennington JM; Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA. Electronic address: jamie.pennington@oregonstate.edu., Uesugi SL; Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA. Electronic address: sandra.uesugi@oregonstate.edu., Labut EM; Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA. Electronic address: Ed.Labut@oregonstate.edu., Vertel EA; Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA. Electronic address: vertele@oregonstate.edu., Anderson KA; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA; NIEHS Superfund Research Program, Oregon State University, Corvallis, OR, 97331, USA. Electronic address: kim.anderson@oregonstate.edu., Tidwell LG; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA. Electronic address: lane.tidwell@oregonstate.edu., Tilton SC; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA; NIEHS Superfund Research Program, Oregon State University, Corvallis, OR, 97331, USA. Electronic address: susan.tilton@oregonstate.edu., Ognibene TJ; Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA, 94550, USA. Electronic address: ognibene1@llnl.gov., Turteltaub KW; Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA, 94550, USA; Biology and Biotechnology Research Division, Lawrence Livermore National Laboratory, Livermore, CA, 94550, USA. Electronic address: turteltaub2@llnl.gov., Smith JN; NIEHS Superfund Research Program, Oregon State University, Corvallis, OR, 97331, USA; Chemical Biology and Exposure Science, Pacific Northwest National Laboratory, Richland, WA, 99354, USA. Electronic address: jordan.smith@pnnl.gov., Williams DE; Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA; NIEHS Superfund Research Program, Oregon State University, Corvallis, OR, 97331, USA.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2023 Sep 01; Vol. 382, pp. 110608. Date of Electronic Publication: 2023 Jun 25.
DOI: 10.1016/j.cbi.2023.110608
Abstrakt: Current risk assessments for environmental carcinogens rely on animal studies utilizing doses orders of magnitude higher than actual human exposures. Epidemiological studies of people with high exposures (e.g., occupational) are of value, but rely on uncertain exposure data. In addition, exposures are typically not to a single chemical but to mixtures, such as polycyclic aromatic hydrocarbons (PAHs). The extremely high sensitivity of accelerator mass spectrometry (AMS) allows for dosing humans with known carcinogens with de minimus risk. In this study UPLC-AMS was used to assess the toxicokinetics of [ 14 C]-benzo[a]pyrene ([ 14 C]-BaP) when dosed alone or in a binary mixture with phenanthrene (Phe). Plasma was collected for 48 h following a dose of [ 14 C]-BaP (50 ng, 5.4 nCi) or the same dose of [ 14 C]-BaP plus Phe (1250 ng). Following the binary mixture, C max of [ 14 C]-BaP significantly decreased (4.4-fold) whereas the volume of distribution (V d ) increased (2-fold). Further, the toxicokinetics of twelve [ 14 C]-BaP metabolites provided evidence of little change in the metabolite profile of [ 14 C]-BaP and the pattern was overall reduction consistent with reduced absorption (decrease in C max ). Although Phe was shown to be a competitive inhibitor of the major hepatic cytochrome P-450 (CYP) responsible for metabolism of [ 14 C]-BaP, CYP1A2, the high inhibition constant (K i ) and lack of any increase in unmetabolized [ 14 C]-BaP in plasma makes this mechanism unlikely to be responsible. Rather, co-administration of Phe reduces the absorption of [ 14 C]-BaP through a mechanism yet to be determined. This is the first study to provide evidence that, at actual environmental levels of exposure, the toxicokinetics of [ 14 C]-BaP in humans is markedly altered by the presence of a second PAH, Phe, a common component of environmental PAH mixtures.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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