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Isolation of a New Mouse 3ß-Hydroxysteroid Dehydrogenase Isoform, 3ß-HSD VI, Expressed During Early Pregnancy¹

Department of Obstetrics and Gynecology (I.G.A., C-H.J.P., A.H.P.), Reproductive Sciences Program (I.G.A., C-H.J.P., A.H.P.), Department of Biological Chemistry (A.H.P.), and Department of Pediatrics (J.Z.K-V.), The University of Michigan, Ann Arbor, Michigan 48109; Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University Medical Center (I.G.A., A.H.P.), Stanford, California 94305; and Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem (J.A., J.O.), Jerusalem 91904, Israel

Address all correspondence and requests for reprints to: Anita H. Payne, Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University Medical Center, 300 Pasteur Drive, Stanford, California 94305.

The enzyme 3ß-hydroxysteroid dehydrogenase (3ß-HSD) is a key enzyme in the biosynthesis of steroid hormones. To date, this laboratory has isolated and characterized five distinct 3ß-HSD complementary DNAs (cDNAs) in the mouse (3ß-HSD I through V). These different forms are expressed in a tissue- and developmentally-specific manner and fall into two functionally distinct enzymes. 3ß-HSD I and III, and most likely II, function as dehydrogenase/isomerases, whereas 3ß-HSD IV and V function as 3-ketosteroid reductases. This study describes the isolation, characterization, and tissue-specific expression of a sixth member of this gene family, 3ß-HSD VI. This new isoform functions as an NAD⁺-dependent dehydrogenase/isomerase exhibiting very low Michaelis-Menten constant (K_m) values for pregnenolone (0.035 µM) and dehydroepiandrosterone (0.12 µM). 3ß-HSD VI is the earliest isoform to be expressed during embryogenesis in cells of embryonic origin at 7 and 9.5 days postcoitum (pc), and is the major isoform expressed in uterine tissue at the time of implantation (4.5 days pc) and continues to be expressed in uterine tissue at 6.5, 7.5, and 9.5 days pc. 3ß-HSD VI is expressed in giant trophoblasts at 9.5 days pc and is expressed in the placenta through day 15.5 pc. In the adult mouse, 3ß-HSD VI appears to be the only isoform expressed in the skin and also is expressed in the testis, but to a lesser extent than 3ß-HSD I. Mouse 3ß-HSD VI cDNA is orthologous to human 3ß-HSD I cDNA. Human type I 3ß-HSD has been shown to be the only isoform expressed in the placenta and skin. The demonstration that mouse 3ß-HSD VI functions as a dehydrogenase/isomerase and is the predominant isoform expressed during the first half of pregnancy in uterine tissue and in embryonic cells suggests that this isoform may be involved in local production of progesterone, which is needed for successful implantation of the blastocyst and/or maintenance of early pregnancy.

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