Tri-substituted organotin compounds, but not retinoic acid, are potent ligands of complement component 8 γ

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  • Yamamoto Katsuya
    Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University
  • Hiromori Youhei
    Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science
  • Matsumaru Daisuke
    Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University
  • Ishii Yoichiro
    Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University
  • Takeshita Yuki
    Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University
  • Tsubakihara Iori
    Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University
  • Kimura Tomoki
    Department of Life Science, Faculty of Science and Engineering, Setsunan University
  • Nagase Hisamitsu
    Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University Faculty of Pharmaceutical Sciences, Gifu University of Medical Science
  • Nakanishi Tsuyoshi
    Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University

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Abstract

<p>Complement component 8 γ (C8γ) is a subunit of complement protein 8 (C8), which itself is a subunit of the complement cytolytic membrane attack complex. However, C8γ is also suggested to be a carrier protein for the general clearance of endogenous and exogenous compounds because it belongs to the lipocalin family of small secreted proteins that have the common ability to bind small hydrophobic ligands. Although retinoic acid, a metabolite of vitamin A, has been suggested as a potential ligand of C8γ, it remains unclear which other substances are able to bind to C8γ as ligands. Here, we evaluated the binding affinity of several organotin compounds that are ligands of a receptor of retinoic acid, retinoid X receptor, by using radioligand binding assays. The amount of [14C]triphenyltin (TPT), a tri-substituted organotin, that bound to purified recombinant C8γ was increased with increasing protein concentration, whereas that of [3H]all-trans retinoic acid and [3H]9-cis retinoic acid was unchanged. Scatchard analysis revealed that [14C]TPT bound to C8γ with an equilibrium dissociation constant (Kd) of 56.2 ± 16.2 nM. Non-radiolabeled tributyltin (TBT), another tri-substituted organotin, blocked the binding of [14C]TPT to C8γ in a competitive manner, but non-radiolabeled mono- or di-substituted organotin compounds did not. Together, our present observations indicate that TBT and TPT, but not retinoic acid or mono- or di-substituted organotin compounds, are potent ligands of C8γ, suggesting that C8γ may be involved in the toxicities of these organotin compounds.</p>

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