The Experts below are selected from a list of 84 Experts worldwide ranked by ideXlab platform
Jianshe Wang - One of the best experts on this subject based on the ideXlab platform.
-
δ4 3 Oxosteroid 5β reductase deficiency responses to oral bile acid therapy and long term outcomes
World Journal of Gastroenterology, 2019Co-Authors: Meihong Zhang, Jing Zhao, Kenneth Dr Setchell, Jingyu Gong, Yi Lu, Jianshe WangAbstract:BACKGROUND Disorders of primary bile acid synthesis may be life-threatening if undiagnosed, or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-Oxosteroid 5β-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid (CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic acid, which is currently unavailable in China.
-
primary 4 3 Oxosteroid 5β reductase deficiency two cases in china
World Journal of Gastroenterology, 2012Co-Authors: Jing Zhao, Lingjuan Fang, Kenneth Dr Setchell, Rui Chen, Liting Li, Jianshe WangAbstract:Aldo-keto reductase 1D1 (AKR1D1) deficiency, a rare but life-threatening form of bile acid deficiency, has not been previously described in China. Here, we describe the first two primary ∆4-3-Oxosteroid 5β-reductase deficiency patients in Mainland China diagnosed by fast atom bombardment-mass spectroscopy of urinary bile acids and confirmed by genetic analysis. A high proportion of atypical 3-oxo-∆4-bile acids in the urine indicated a deficiency in ∆4-3-Oxosteroid 5β-reductase. All of the coding exons and adjacent intronic sequence of the AKR1D1 gene were sequenced using peripheral lymphocyte genomic DNA of two patients and one of the patient’s parents. One patient exhibited compound heterozygous mutations: c.396C>A and c.722A>T, while the other was heterozygous for the mutation c.797G>A. Based on these mutations, a diagnosis of primary ∆4-3-Oxosteroid 5β-reductase deficiency could be confirmed. With ursodeoxycholic acid treatment and fat-soluble vitamin supplements, liver function tests normalized rapidly, and the degree of hepatomegaly was markedly reduced in both patients.
Fernand Labire - One of the best experts on this subject based on the ideXlab platform.
-
the enzyme and inhibitors of 4 ene 3 Oxosteroid 5α oxidoreductase
Steroids, 1995Co-Authors: Xun Li, Cailin Chen, Shankar M Singh, Fernand LabireAbstract:Abstract Since evidence of 5α-reductase activity in rabbit liver homogenate was discovered in 1954, the presence of this enzyme has been demonstrated in many other organs and tissues of mammalian species. 5α-Reductase selectively transforms a 4-ene-3-Oxosteroid (e.g., testosterone) irreversibly to the corresponding 5α-3-Oxosteroid (e.g., 5α-dihydrotestosterone) in the presence of NADPH as an essential coenzyme at an optimal pH. However, excessive production of 5α-dihydrotestosterone is the major cause of many androgen-related disorders, such as prostate cancer, benign prostatic hyperplasia, acne, female hirsutism, and male pattern baldness; therefore, inhibition of androgenic action by 5α-reductase inhibitors is a logical treatment. During the past two decades, research has focused on understanding the biological functions and effects of 5α-reductase and its 5α-reduced metabolites: purification of the enzyme, substrates, and metabolites: characterization of their physical, chemical, and biochemical properties; analysis of the amino acid sequence of the enzyme; synthesis of various classes of molecules as potential inhibitors; and examination of the biological activity of the inhibitors in vitro and/or in vivo. This review summarizes the biochemical studies on this enzyme, suggests the mechanisms of action of the enzyme or inhibitors, and discusses the chemistry necessary for the preparation, structure-activity relationships, and in vitro and/or in vivo data obtained from the evaluation of nonsteroidal and steroidal compounds that have been tested as inhibitors of 5α-reductase. In particular, IC 50 and K i values for relevant compounds will be compared according to molecular class. This review could function as a comprehensive working reference of what research has been accomplished so far and what problems remain to be solved in the future for those engaged in this interesting field.
Jing Zhao - One of the best experts on this subject based on the ideXlab platform.
-
δ4 3 Oxosteroid 5β reductase deficiency responses to oral bile acid therapy and long term outcomes
World Journal of Gastroenterology, 2019Co-Authors: Meihong Zhang, Jing Zhao, Kenneth Dr Setchell, Jingyu Gong, Yi Lu, Jianshe WangAbstract:BACKGROUND Disorders of primary bile acid synthesis may be life-threatening if undiagnosed, or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-Oxosteroid 5β-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid (CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic acid, which is currently unavailable in China.
-
primary 4 3 Oxosteroid 5β reductase deficiency two cases in china
World Journal of Gastroenterology, 2012Co-Authors: Jing Zhao, Lingjuan Fang, Kenneth Dr Setchell, Rui Chen, Liting Li, Jianshe WangAbstract:Aldo-keto reductase 1D1 (AKR1D1) deficiency, a rare but life-threatening form of bile acid deficiency, has not been previously described in China. Here, we describe the first two primary ∆4-3-Oxosteroid 5β-reductase deficiency patients in Mainland China diagnosed by fast atom bombardment-mass spectroscopy of urinary bile acids and confirmed by genetic analysis. A high proportion of atypical 3-oxo-∆4-bile acids in the urine indicated a deficiency in ∆4-3-Oxosteroid 5β-reductase. All of the coding exons and adjacent intronic sequence of the AKR1D1 gene were sequenced using peripheral lymphocyte genomic DNA of two patients and one of the patient’s parents. One patient exhibited compound heterozygous mutations: c.396C>A and c.722A>T, while the other was heterozygous for the mutation c.797G>A. Based on these mutations, a diagnosis of primary ∆4-3-Oxosteroid 5β-reductase deficiency could be confirmed. With ursodeoxycholic acid treatment and fat-soluble vitamin supplements, liver function tests normalized rapidly, and the degree of hepatomegaly was markedly reduced in both patients.
Ingemar Bjorkhem - One of the best experts on this subject based on the ideXlab platform.
-
Cloning and expression of cDNA of human Δ4‐3‐Oxosteroid 5β‐reductase and substrate specificity of the expressed enzyme
FEBS Journal, 1994Co-Authors: Kazu‐hiro Kondo, Yoshiko Setoguchi, Gosta Eggertsen, Peter Sjoblom, Toshiaki Setoguchi, Kyu‐ichiro Okuda, Ingemar BjorkhemAbstract:The enzyme Δ4-3-Oxosteroid 5β-reductase (3-oxo-5β-steroid: NADP+ oxidoreductase and 4,5β-dihydrocortisone: NADP+Δ4-oxidoreductase) catalyzes the reduction of the Δ4 double bond of bile acid intermediates and steroid hormones carrying the Δ4-3-one structure in the A/B cis configuration. Human Δ4-3-Oxosteroid 5β-reductase cDNA was isolated from a liver cDNA library by cross hybridization with a previously cloned rat cDNA, which was used as a probe [Onishi, Y., Noshiro, M., Shimosato, T. & Okuda, K.-I. (1991) FEBS Lett. 283, 215–218]. DNA sequence analysis of a hybridization-positive clone predicted the human Δ4-3-Oxosteroid 5β-reductase to contain 326 amino acids. The amino acid sequence of the human Δ4-3-Oxosteroid 5β-reductase had 79% overall identity to the rat enzyme sequence. It also showed 54% and 50% overall identity with rat 3α-hydroxysteroid dehydrogenase and human aldose reductase, respectively. RNA blotting analysis demonstrated the existence of a single Δ4-3-Oxosteroid 5β-reductase mRNA of approximately 2.7 kb in human liver. Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7α,12α-dihydroxy-4-cholesten-3-one and 7α-hydroxy-4-cholesten-3-one. In addition, the expressed enzyme showed a small but significant 5β-reduction activity toward 11β,17α,21-trihydroxy-Δ4-pregnene-3,20-dione (cortisol) and 17β-hydroxy-Δ4-androsten-3-one (testosterone) whereas no activity was observed toward Δ4-pregnene-3,20-dione (progesterone) or Δ4-androstene-3-17-dione (androstenedione). The substrate specificity of the human enzyme is considerably narrower than that of the rat enzyme, and the enzyme seems to be more important for bile acid biosynthesis than for metabolism of steroid hormones.
-
cloning and expression of cdna of human δ4 3 Oxosteroid 5β reductase and substrate specificity of the expressed enzyme
FEBS Journal, 1994Co-Authors: Kazuhiro Kondo, Kyuichiro Okuda, Yoshiko Setoguchi, Gosta Eggertsen, Peter Sjoblom, Toshiaki Setoguchi, Ingemar BjorkhemAbstract:The enzyme Δ4-3-Oxosteroid 5β-reductase (3-oxo-5β-steroid: NADP+ oxidoreductase and 4,5β-dihydrocortisone: NADP+Δ4-oxidoreductase) catalyzes the reduction of the Δ4 double bond of bile acid intermediates and steroid hormones carrying the Δ4-3-one structure in the A/B cis configuration. Human Δ4-3-Oxosteroid 5β-reductase cDNA was isolated from a liver cDNA library by cross hybridization with a previously cloned rat cDNA, which was used as a probe [Onishi, Y., Noshiro, M., Shimosato, T. & Okuda, K.-I. (1991) FEBS Lett. 283, 215–218]. DNA sequence analysis of a hybridization-positive clone predicted the human Δ4-3-Oxosteroid 5β-reductase to contain 326 amino acids. The amino acid sequence of the human Δ4-3-Oxosteroid 5β-reductase had 79% overall identity to the rat enzyme sequence. It also showed 54% and 50% overall identity with rat 3α-hydroxysteroid dehydrogenase and human aldose reductase, respectively. RNA blotting analysis demonstrated the existence of a single Δ4-3-Oxosteroid 5β-reductase mRNA of approximately 2.7 kb in human liver. Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7α,12α-dihydroxy-4-cholesten-3-one and 7α-hydroxy-4-cholesten-3-one. In addition, the expressed enzyme showed a small but significant 5β-reduction activity toward 11β,17α,21-trihydroxy-Δ4-pregnene-3,20-dione (cortisol) and 17β-hydroxy-Δ4-androsten-3-one (testosterone) whereas no activity was observed toward Δ4-pregnene-3,20-dione (progesterone) or Δ4-androstene-3-17-dione (androstenedione). The substrate specificity of the human enzyme is considerably narrower than that of the rat enzyme, and the enzyme seems to be more important for bile acid biosynthesis than for metabolism of steroid hormones.
Kyuichiro Okuda - One of the best experts on this subject based on the ideXlab platform.
-
cloning and expression of cdna of human δ4 3 Oxosteroid 5β reductase and substrate specificity of the expressed enzyme
FEBS Journal, 1994Co-Authors: Kazuhiro Kondo, Kyuichiro Okuda, Yoshiko Setoguchi, Gosta Eggertsen, Peter Sjoblom, Toshiaki Setoguchi, Ingemar BjorkhemAbstract:The enzyme Δ4-3-Oxosteroid 5β-reductase (3-oxo-5β-steroid: NADP+ oxidoreductase and 4,5β-dihydrocortisone: NADP+Δ4-oxidoreductase) catalyzes the reduction of the Δ4 double bond of bile acid intermediates and steroid hormones carrying the Δ4-3-one structure in the A/B cis configuration. Human Δ4-3-Oxosteroid 5β-reductase cDNA was isolated from a liver cDNA library by cross hybridization with a previously cloned rat cDNA, which was used as a probe [Onishi, Y., Noshiro, M., Shimosato, T. & Okuda, K.-I. (1991) FEBS Lett. 283, 215–218]. DNA sequence analysis of a hybridization-positive clone predicted the human Δ4-3-Oxosteroid 5β-reductase to contain 326 amino acids. The amino acid sequence of the human Δ4-3-Oxosteroid 5β-reductase had 79% overall identity to the rat enzyme sequence. It also showed 54% and 50% overall identity with rat 3α-hydroxysteroid dehydrogenase and human aldose reductase, respectively. RNA blotting analysis demonstrated the existence of a single Δ4-3-Oxosteroid 5β-reductase mRNA of approximately 2.7 kb in human liver. Transfection of the cDNA into COS cells resulted in the expression of an active enzyme with a high activity toward the bile acid intermediates 7α,12α-dihydroxy-4-cholesten-3-one and 7α-hydroxy-4-cholesten-3-one. In addition, the expressed enzyme showed a small but significant 5β-reduction activity toward 11β,17α,21-trihydroxy-Δ4-pregnene-3,20-dione (cortisol) and 17β-hydroxy-Δ4-androsten-3-one (testosterone) whereas no activity was observed toward Δ4-pregnene-3,20-dione (progesterone) or Δ4-androstene-3-17-dione (androstenedione). The substrate specificity of the human enzyme is considerably narrower than that of the rat enzyme, and the enzyme seems to be more important for bile acid biosynthesis than for metabolism of steroid hormones.
-
delta 4-3-Oxosteroid 5 beta-reductase. Structure and function.
Biological chemistry Hoppe-Seyler, 1991Co-Authors: Yoshiaki Onishi, Mitsuhide Noshiro, Tsunehiro Shimosato, Kyuichiro OkudaAbstract:delta 4-3-Oxosteroid 5 beta-reductase catalysing reduction of delta 4-3-Oxosteroids to give A/B cis-conformation was intraperitoneally injected into BALB/c strain mice with Ribi adjuvant. Monoclonal antibody specific for this enzyme was prepared from their spleen cells. Using this monoclonal antibody as a probe the enzyme was further purified using reversed phase liquid chromatography to determine amino-acid sequence protein-chemically. Attempts to determine the N-terminal amino acid failed, indicating that the N-terminal amino acid is blocked. The protein was therefore subjected to digestion with lysyl endopeptidase after alkylating with iodoacetate. The peptides thus formed were isolated and purified by reversed-phase high-performance liquid chromatography and their amino-acid sequences were determined. Using antibodies and oligonucleotides as probes a cDNA which contained a 978 bp long open reading frame encoding 326 amino-acid residues (Mr 37376) was isolated from rat liver cDNA libraries and the entire sequence of the protein was deciphered from its nucleotide sequence. The COS cells transfected with this cDNA revealed a versatile activity to reduce varied kinds of delta 4-3-Oxosteroids, i.e. 7 alpha-hydroxy-4-cholesten-3-one, androstenedione and cortisone as postulated by Okuda and Okuda (1984, J. Biol. Chem. 259, 7519-7524) and Furuebisu et al. (1987, Biochim. Biophys. Acta 912, 110-114. With a newly established immunoblotting assay method several tissues and organs were surveyed and it was found that the enzyme exists only in the liver and there is an apparent difference between sexes as to the content of this enzyme. However, there was little if any difference in the amount of mRNAs between both sexes, which may indicates that the sexual difference of rat liver cytosol 5 beta-reductase is due to a posttranslational modification and/or degradation.
