Isolation of a new mouse 3-hydroxysteroid dehydrogenase isoform, 3 beta-HSD VI, expressed during early pregnancy

The enzyme 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) is a key enzyme in the biosynthesis of steroid hormones. To date, this laboratory has isolated and characterized five distinct 3 beta-HSD complementary DNAs (cDNAs) in the mouse (3 beta-HSD I through V). These different forms are expressed in a tissue- and developmentally-specific manner and fall into two functionally distinct enzymes. 3 beta-HSD I and III, and most likely II, function as dehydrogenase/isomerases, whereas 3 beta-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, 3 beta-HSD VI. This neu; isoform functions as an NAD(+)-dependent dehydrogenase/isomerase exhibiting very low Michaelis-Menten constant (K-m) values for pregnenolone (similar to 0.035 mu M) and dehydrocpiandrosterone (similar to 0.12 mu M). 3 beta-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 Co be expressed in uterine tissue at 6.5, 7.5, and 9.5 days pc. 3 beta-HSD VI is expressed in giant trophoblasts at 9.5 days pc and is expressed in the placenta through day 15.6 pc. In the adult mouse, 3 beta-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 3 beta-HSD I. Mouse 3 beta-HSD VI cDNA is orthologous to human 3 beta-HSD I cDNA. Human type I 3 beta-HSD has been shown to be the only isoform expressed in the placenta and skin. The demonstration that mouse 3 beta-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.