Masuda Tomoyuki, Ishii Kazuhiro, Morishita Yukio, Iwasaki Nobuaki, Shibata Yasuyuki, Tamaoka Akira
Department of Neurology, Faculty of Medicine, University of Tsukuba.
Department of Neurobiology, Faculty of Medicine, University of Tsukuba.
J Toxicol Sci. 2018;43(5):291-298. doi: 10.2131/jts.43.291.
Organic arsenic diphenylarsinic acid (DPAA[V]) accumulates at high concentrations in the liver of primates after its subchronic administration. However, no studies on the hepatic effects of organic arsenic compounds, including DPAA(V), on primates have been reported to date. To clarify the toxicokinetics of DPAA(V) in the liver of primates, hepatic tissue specimens were collected from cynomolgus monkeys (n = 32) at 5, 29, 170, and 339 days after repeated administration of DPAA(V) for 28 days. Four histopathological changes in the specimens were observed and pathologically evaluated. Atypical ductular proliferation was found in the DPAA(V)-exposed liver throughout the period. Inflammatory cell infiltration in Glisson's capsules and lipid droplets were seen at earlier periods after administration. Conversely, inflammatory cell infiltration in liver lobules was seen later after administration. In this experiment, we did not confirm the hepatic dysfunction of DPAA(V)-exposed monkeys by blood chemistry tests. To compensate for this, we further investigated the blood from a patient who exhibited several neurological symptoms after DPAA(V) exposure. Her blood chemistry test values for aspartate transaminase, alanine transaminase, and lactate dehydrogenase were elevated, suggesting that her liver may have been damaged by DPAA(V) exposure. Together, these findings suggest that the accumulation of DPAA(V) may induce differential histopathological changes in primate hepatocytes, resulting in decreased liver function. This is the first report to investigate the liver of primates pathologically after exposure to organic arsenic DPAA(V). Our findings will help expand our knowledge regarding the effect of DPAA(V) on the liver of primates.
在灵长类动物亚慢性给予有机砷二苯基次胂酸（DPAA[V]）后，其在肝脏中会高浓度蓄积。然而，迄今为止，尚未见包括DPAA(V)在内的有机砷化合物对灵长类动物肝脏影响的研究报道。为阐明DPAA(V)在灵长类动物肝脏中的毒代动力学，在对食蟹猴（n = 32）重复给予DPAA(V) 28天后，于第5、29、170和339天采集肝脏组织标本。观察并对标本中的四种组织病理学变化进行病理评估。在整个观察期内，暴露于DPAA(V)的肝脏中均发现了非典型小胆管增生。给药早期可见Glisson囊内炎性细胞浸润和脂滴。相反，给药后期可见肝小叶内炎性细胞浸润。在本实验中，我们通过血液生化检测未证实DPAA(V)暴露猴存在肝功能障碍。为此，我们进一步研究了一名在暴露于DPAA(V)后出现多种神经症状患者的血液。她的天冬氨酸转氨酶、丙氨酸转氨酶和乳酸脱氢酶的血液生化检测值升高，提示其肝脏可能因DPAA(V)暴露而受损。这些发现共同表明，DPAA(V)的蓄积可能在灵长类动物肝细胞中诱导不同的组织病理学变化，导致肝功能下降。这是首篇对灵长类动物经有机砷DPAA(V)暴露后肝脏进行病理学研究的报告。我们的研究结果将有助于拓展我们对DPAA(V)对灵长类动物肝脏影响的认识。
