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J. Biol. Chem., Vol. 283, Issue 17, 11270-11279, April 25, 2008

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Conversion of Phylloquinone (Vitamin K₁) into Menaquinone-4 (Vitamin K₂) in Mice

TWO POSSIBLE ROUTES FOR MENAQUINONE-4 ACCUMULATION IN CEREBRA OF MICE^*

Toshio Okano¹, Yuka Shimomura, Makiko Yamane, Yoshitomo Suhara, Maya Kamao, Makiko Sugiura, and Kimie Nakagawa

From the Department of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558 and the Analytical Center, Kobe Pharmaceutical University, Kobe 658-8558, Japan

There are two forms of naturally occurring vitamin K, phylloquinone and the menaquinones. Phylloquinone (vitamin K₁) is a major type (>90%) of dietary vitamin K, but its concentrations in animal tissues are remarkably low compared with those of the menaquinones, especially menaquinone-4 (vitamin K₂), the major form (>90%) of vitamin K in tissues. Despite this great difference, the origin of tissue menaquinone-4 has yet to be exclusively defined. It is postulated that phylloquinone is converted into menaquinone-4 and accumulates in extrahepatic tissues. To clarify this, phylloquinone with a deuterium-labeled 2-methyl-1,4-naphthoquinone ring was given orally to mice, and cerebra were collected for D NMR and liquid chromatography-tandem mass spectrometry analyses. We identified the labeled menaquinone-4 that was converted from the given phylloquinone, and this conversion occurred following an oral or enteral administration, but not parenteral or intracerebroventricular administration. By the oral route, the phylloquinone with the deuterium-labeled side chain in addition to the labeled 2-methyl-1,4-naphthoquinone was clearly converted into a labeled menaquinone-4 with a non-deuterium-labeled side chain, implying that phylloquinone was converted into menaquinone-4 via integral side-chain removal. The conversion also occurred in cerebral slice cultures and primary cultures. Deuterium-labeled menadione was consistently converted into the labeled menaquinone-4 with all of the administration routes and the culture conditions tested. Our results suggest that cerebral menaquinone-4 originates from phylloquinone intake and that there are two routes of accumulation, one is the release of menadione from phylloquinone in the intestine followed by the prenylation of menadione into menaquinone-4 in tissues, and another is cleavage and prenylation within the cerebrum.

Received for publication, April 9, 2007 , and in revised form, December 12, 2007.

^* This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 81-78-441-7563; Fax: 81-78-441-7565; E-mail: t-okano{at}kobepharma-u.ac.jp.

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