Molecular cloning of two human liver 3 α-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder

Deyashiki, Yoshihiro; Ogasawara, Akihito; Nakayama, Toshihiro; Nakanishi, Mahito; Miyabe, Yuki; Sato, Kumiko; Hara, Akira

doi:10.1042/bj2990545

Cited by 95 publications

(73 citation statements)

References 32 publications

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“…It did not convert DHP to allopregnanolone but converted androgens such as 5␣-dihydrotestosterone (5␣-androstan-17␤-ol-3-one) to andro- (21,33); human type 3 is also bile acid binding protein (31); human 20␣HSD is also DD1 (34, 35); x, no amino acid (rat 3␣HSD is one amino acid shorter than the human forms). stanediol (5␣-androstan-3␣, 17␤-diol).…”

Section: Resultsmentioning

confidence: 99%

Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes

Griffin

Mellon

1999

Proc. Natl. Acad. Sci. U.S.A.

364

217

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The neurosteroid 3␣-hydroxysteroid-5␣-pregnan-20-one (allopregnanolone) acts as a positive allosteric modulator of ␥-aminobutyric acid at ␥-aminobutyric acid type A receptors and hence is a powerful anxiolytic, anticonvulsant, and anesthetic agent. Allopregnanolone is synthesized from progesterone by reduction to 5␣-dihydroprogesterone, mediated by 5␣-reductase, and by reduction to allopregnanolone, mediated by 3␣-hydroxysteroid dehydrogenase (3␣-HSD). Previous reports suggested that some selective serotonin reuptake inhibitors (SSRIs) could alter concentrations of allopregnanolone in human cerebral spinal fluid and in rat brain sections. We determined whether SSRIs directly altered the activities of either 5␣-reductase or 3␣-HSD, using an in vitro system containing purified recombinant proteins. Although rats appear to express a single 3␣-HSD isoform, the human brain contains several isoforms of this enzyme, including a new isoform we cloned from human fetal brains. Our results indicate that the SSRIs fluoxetine, sertraline, and paroxetine decrease the Km of the conversion of 5␣-dihydroprogesterone to allopregnanolone by human 3␣-HSD type III 10-to 30-fold. Only sertraline inhibited the reverse oxidative reaction. SSRIs also affected conversions of androgens to 3␣-and 3␣, 17␤-reduced or -oxidized androgens mediated by 3␣-HSD type IIBrain. Another antidepressant, imipramine, was without any effect on allopregnanolone or androstanediol production. The region-specific expression of 3␣-HSD type IIBrain and 3␣-HSD type III mRNAs suggest that SSRIs will affect neurosteroid production in a region-specific manner. Our results may thus help explain the rapid alleviation of the anxiety and dysphoria associated with late luteal phase dysphoria disorder and major unipolar depression by these SSRIs.3␣ hydroxysteroid dehydrogenase ͉ fluoxetine ͉ allopregnanolone ͉ dihydroprogesterone

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Section: Resultsmentioning

confidence: 99%

Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes

Griffin

Mellon

1999

Proc. Natl. Acad. Sci. U.S.A.

364

217

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“…This recombinant enzyme has mainly 17b-HSD activity to metabolize oestrogens and androgens, and also catalyses the one-way reaction from 20a-OHP to progesterone. Thereafter, cDNA encoding a cytosolic enzyme dihydrodiol dehydrogenase (DD) 1 in human liver was cloned and recently identi®ed as human 20a-HSD [AKR 1C1] cDNA (Stolz et al 1993;Deyashiki et al 1994;Hara et al 1996). This 323 amino acid residue-protein has 80% and 69% amino acid identity to rabbit and rat 20a-HSDs, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…This 323 amino acid residue-protein has 80% and 69% amino acid identity to rabbit and rat 20a-HSDs, respectively. Surprisingly, it has a much higher amino acid identity to other human liver AKRs: 98% to bile acid-binding protein (BABP)/DD2 [AKR 1C2] ; 88% to prostaglandin F synthase (PGFS)/3a-HSD type 2 [AKR 1C3] (Khanna et al 1995b;Nagase et al 1995;Suzuki-Yamamoto et al 1999); and 83% to DD4/chlordecone reductase/3a-HSD type 1 [AKR 1C4] (Winters et al 1990;Qin et al 1993;Deyashiki et al 1994). Due to the extremely high homology among these AKR members, cDNA probes and antibodies can hardly discriminate 20a-HSD from the others by Northern and Western blot analyses.…”

Section: Introductionmentioning

confidence: 99%

Close kinship of human 20α‐hydroxysteroid dehydrogenase gene with three aldo‐keto reductase genes

Nishizawa¹,

et al. 2000

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Background: 20a-Hydroxysteroid dehydrogenase (HSD) is a member of the aldo-keto reductase (AKR) superfamily and catalyses the reaction of progesterone to the inactive form 20a-hydroxyprogesterone. Progesterone plays an important role in the maintenance of pregnancy, and, in rodents, plasma progesterone levels decrease abruptly just before parturition. The induction of 20a-HSD is thought to be responsible for the decrease in plasma progesterone at term. High homology between human 20a-HSD [AKR 1C1] cDNA with other AKRs had caused dif®culty in gene isolation and expression analysis. Thus, the metabolism of progesterone in the human reproductive system remained unclear.

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“…Recombinant phages coding for DD antigen were identified by the plaque-screening method [23] with E. coli Y1090 as the host ; immunopositive pharge plaques were detected as described previously [24]. The cDNA inserts (approx.…”

Section: Primermentioning

confidence: 99%

“…The cDNA inserts (approx. 750 bp) from the positive clones were subcloned into EcoRI site of pBluescript II plasmids ; the nucleotide sequences of the cDNA species were determined as described [24].…”

Section: Primermentioning

confidence: 99%

Cloning and sequencing of the cDNA species for mammalian dimeric dihydrodiol dehydrogenases

Arimitsu

Aoki

Ishikura

et al. 1999

Biochemical Journal

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Cynomolgus and Japanese monkey kidneys, dog and pig livers and rabbit lens contain dimeric dihydrodiol dehydrogenase (EC 1.3.1.20) associated with high carbonyl reductase activity. Here we have isolated cDNA species for the dimeric enzymes by reverse transcriptase-PCR from human intestine in addition to the above five animal tissues. The amino acid sequences deduced from the monkey, pig and dog cDNA species perfectly matched the partial sequences of peptides digested from the respective enzymes of these animal tissues, and active recombinant proteins were expressed in a bacterial system from the monkey and human cDNA species. Northern blot analysis revealed the existence of a single 1.3 kb mRNA species for the enzyme in these animal tissues. The human enzyme shared 94%, 85%, 84% and 82% amino acid identity with the enzymes of the two monkey strains (their sequences were identical), the dog, the pig and the rabbit respectively. The sequences of the primate enzymes consisted of 335 amino acid residues and lacked one amino acid compared with the other animal enzymes. In contrast with previous reports that other types of dihydrodiol dehydrogenase, carbonyl reductases and enzymes with either activity belong to the aldo-keto reductase family or the short-chain dehydrogenase/reductase family, dimeric dihydrodiol dehydrogenase showed no sequence similarity with the members of the two protein families. The dimeric enzyme aligned with low degrees of identity (14-25%) with several prokaryotic proteins, in which 47 residues are strictly or highly conserved. Thus dimeric dihydrodiol dehydrogenase has a primary structure distinct from the previously known mammalian enzymes and is suggested to constitute a novel protein family with the prokaryotic proteins.

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Molecular cloning of two human liver 3 α-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder

Cited by 95 publications

References 32 publications

Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes

Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes

Close kinship of human 20α‐hydroxysteroid dehydrogenase gene with three aldo‐keto reductase genes

Cloning and sequencing of the cDNA species for mammalian dimeric dihydrodiol dehydrogenases

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