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A more recent version of this article appeared on January 12, 2001
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Papers In Press, published online ahead of print November 13, 2000
J. Biol. Chem, 10.1074/jbc.C000676200
Submitted on September 27, 2000
Revised on November 10, 2000
Accepted on November 13, 2000

Alpha-tocopherol transfer protein is important for the normal development of placental labyrinthine trophoblasts in mice

Kou-ichi Jishage, Makoto Arita, Keiji Igarashi, Takamitsu Iwata, Miho Watanabe, Masako Ogawa, Otoya Ueda, Nobuo Kamada, Keizo Inoue, Hiroyuki Arai, and Hiroshi Suzuki

Pharmaceutical Technology Laboratory, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513

Corresponding Author: suzukihirs{at}gt.chugai-pharm.co.jp

A-tocopherol transfer protein (a-TTP), a cytosolic protein that specifically binds a-tocopherol, is known as a product of the causative gene in patients with ataxia associated with vitamin E deficiency. Targeted disruption of the a-TTP gene revealed that a-tocopherol concentration in the circulation was regulated by a-TTP expression levels. Male a-TTP-/- mice were fertile. However, placentas of pregnant a-TTP-/- females were severely impaired with marked reduction of labyrinthine trophoblasts, and the embryos died at midgestation, even when fertilized eggs of a-TTP+/+ mice were transferred into a-TTP-/- recipients. The use of excess a-tocopherol or a synthetic antioxidant (BO-653) dietary supplement by a-TTP-/- females prevented placental failure and allowed full-term pregnancies. In a-TTP+/+ animals, a-TTP gene expression was observed in the uterus, and its level transiently increased after implantation (4.5 days post-coitum). Our results suggest that oxidative stress in the labyrinth region of the placenta is protected by vitamin E during development, and that in addition to the hepatic a-TTP which governs plasma a-tocopherol level, the uterine a-TTP may also play an important role in supplying this vitamin.


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