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J. Biol. Chem., Vol. 278, Issue 23, 21204-21211, June 6, 2003

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Identification of Outer Mitochondrial Membrane Cytochrome b₅ as a Modulator for Androgen Synthesis in Leydig Cells^*

Tadashi Ogishima ? , Jun-ya Kinoshita ?, Fumiko Mitani , Makoto Suematsu  and Akio Ito ?

From the ^?Department of Chemistry, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan and the Department of Biochemistry and Integrative Medical Biology, Keio University, Tokyo 160-8582, Japan

Outer mitochondrial membrane cytochrome b₅ is an isoform of microsomal membrane cytochrome b₅. In rat testes the outer mitochondrial membrane cytochrome b₅ is present in both mitochondria and microsomes, whereas microsomal membrane cytochrome b₅ is undetectable. Outer mitochondrial membrane cytochrome b₅ present in the testis was localized in Leydig cells with cytochrome P-450₁₇, which catalyzes androgenesis therein. We therefore analyzed the functions of outer mitochondrial membrane cytochrome b₅ in rat testis microsomes by using a proteoliposome system. In a low but physiological concentration of NADPH-cytochrome P-450 reductase and excess amount of progesterone, outer mitochondrial membrane cytochrome b₅ stimulated the cytochrome P-450₁₇-catalyzed reactions, 17-hydroxylation and C17-C20 bond cleavage. The effects were different from those by microsomal membrane cytochrome b₅ as follows: preferential elevation of the 17-hydroxylase activity by outer mitochondrial membrane cytochrome b₅ in an amount-dependent manner versus that of the lyase activity by microsomal membrane cytochrome b₅ at the low concentration, and the inhibition of both activities at the high concentration. At a low concentration of progesterone reflecting a physiological cholesterol supply, outer mitochondrial membrane cytochrome b₅ elevated primarily the production of 17-hydroxyprogesterone and then facilitated the conversion of the released intermediate to androstenedione. Thus, we demonstrated that outer mitochondrial membrane cytochrome b₅ and not microsomal membrane cytochrome b₅ functions as an activator for androgenesis in rat Leydig cells.

Received for publication, February 18, 2003 , and in revised form, March 28, 2003.

^* This work was supported in part grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (to T. O. and A. I.). 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.

To whom correspondence should be addressed. Tel.: 81-92-642-2601; Fax: 81-91-642-2607; E-mail: taogiscc{at}mbox.nc.kyushu-u.ac.jp.

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