髙橋 一聡

Mercury (Hg) is one of the most toxic environmental pollutants, and is biocondensed via the food chain. Selenium (Se) is an essential element that possesses an antagonistic property towards Hg in vivo. The antagonistic property is explained by the assumption that Hg and Se directly interact to form HgSe nanoparticles (HgSe NPs) in organs. It is presumed that the toxic effects of HgSe NPs are lower than that of ionic Hg; however, no precise evaluation has been conducted so far. In the present study, we evaluated the distribution of HgSe NPs ingested in Se-deficient rats. The recovery of serum selenoproteins from a deficient level was not observed in rats orally administered HgSe NPs. In addition, the excretion of Hg and Se via urine was not observed. Interestingly, the biosynthesis of selenoproteins and urinary selenometabolites would have required the production of selenide through the degradation of HgSe NPs. Therefore, it seems that selenide and Hg are not released from HgSe NPs in vivo. The administration of HgSe NPs did not increase Hg and Se concentrations in organs, and almost all HgSe NPs were recovered in feces, indicating no or low bioaccessibility of HgSe NPs even in Se-deficient rats. These results suggest that HgSe NPs are biologically inert and do not become a secondary environmental pollutant of Hg.

Fibulin-4 is a matricellular protein required for extracellular matrix (ECM) assembly. Mice deficient in fibulin-4 (Fbln4-/- ) have disrupted collagen and elastin fibers and die shortly after birth from aortic and diaphragmatic rupture. The function of fibulin-4 in ECM assembly, however, remains elusive. Here, we show that fibulin-4 is required for the activity of lysyl oxidase (LOX), a copper-containing enzyme that catalyzes the covalent cross-linking of elastin and collagen. LOX produced by Fbln4-/- cells had lower activity than LOX produced by wild-type cells due to the absence of lysine tyrosyl quinone (LTQ), a unique cofactor required for LOX activity. Our studies showed that fibulin-4 is required for copper ion transfer from the copper transporter ATP7A to LOX in the trans-Golgi network (TGN), which is a necessary step for LTQ formation. These results uncover a pivotal role for fibulin-4 in the activation of LOX and, hence, in ECM assembly.

Since selenium (Se) is an essential mineral, animals must be able to metabolize the various selenocompounds in meat, fish and vegetables. It is unclear how animals, including humans, utilize selenocompound efficiently, but we hypothesized that gut microflora might contribute to these processes. In this study, we revealed that Se-methylselenocysteine and selenocyanate were metabolized to selenomethionine (SeMet) by intestinal microflora, suggesting selenocompounds might be metabolized to SeMet, which can be used by the host organism. The major urinary selenosugar, 1 beta-methylseleno-N-acetyl-D-galactosamine, was utilized less in microflora-suppressed than healthy rats, suggesting that this sugar can be transformed to a nutritionally available form by gut microflora in animals with a healthy microbiota. We concluded that, in rats at least, gut microflora has a role in the metabolism of Se in the host animal, and this finding might be worth investigating in humans.