Disease relevance of SRD5A1

• OBJECTIVE: The purpose of our study is to investigate the genetic polymorphisms of steroid 5alpha-reductase type 1 and 2 (SRD5A1 and SRD5A2) genes in Korean population, and to study the association of these polymorphisms with the development, clinical types (female or male pattern) and therapeutic response of androgenetic alopecia [1].
• CONCLUSION: Mutant SRD5A1 isoenzyme does not seem to play a crucial role in the development of hypospadias [2].
• RESULTS: Prostate cancer cells express undetectable to low levels of SRD5A2 but elevated levels of SRD5A1 activity compared with nonmalignant prostatic tissue [3].
• Glandular hyperplasia can be partially reversed by withdrawal of androgenic tone with androgen receptor antagonists or steroid-5-alpha-reductase inhibitors [4].
• That only SRD5A1 haplotypes were associated with hirsutism suggests that only this isoform is important in the hair follicle [5].

Psychiatry related information on SRD5A1

• RESULTS: (1) Reaction time (RT) depended on the SR type, indicating SR-specific differences in processing, which did not vary with age [6].

High impact information on SRD5A1

• The conversion of testosterone into dihydrotestosterone by steroid 5 alpha-reductase is a key reaction in androgen action, and is essential both for the formation of the male phenotype during embryogenesis and for androgen-mediated growth of tissues such as the prostate [7].
• Perplexing and difficult problems remain unresolved, e.g. whether the variability in manifestations is due to variable expressions of steroid 5 alpha-reductase 1 or to effects of testosterone itself [8].
• The synthesis of dihydrotestosterone is catalyzed by steroid 5 alpha-reductase isozymes, designated types 1 and 2 [9].
• Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression [9].
• We further show that in contrast to the major steroid 5 alpha-reductase in the prostate and cultured skin fibroblasts, the cDNA-encoded enzyme exhibits a neutral to basic pH optima and is much less sensitive to inhibition by the 4-aza steroid, finasteride (MK-906) [10].

Chemical compound and disease context of SRD5A1

• The enzyme steroid 5 alpha-reductase catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone, and impairment of this reaction causes a form of male pseudohermaphroditism in which genetic males differentiate predominantly as phenotypic females [10].
• As potent inhibitors of human steroid 5 alpha-reductase (SR) the 3-androstene-3-carboxylic acids, or steroidal acrylates, may be useful in treatment of diseases such as benign prostatic hyperplasia for which 5 alpha-dihydrotestosterone (DHT) appears to be a causative agent [11].
• The prostate gland is an androgen-dependent, and polymorphisms in androgen synthesis gene steroid 5-alpha reductase type II (SRD5A2) may be associated with benign prostatic hyperplasia (BPH) and prostate cancer [12].
• PAGE analysis revealed an electrophoretic pattern similar to the SR-type lipopolysaccharide (LPS) of Salmonella [13].

Biological context of SRD5A1

• Genetic linkage to the steroid 5alpha-reductase type 1 gene (SRD5A1) was ruled out in this family [14].
• We conducted genetic association studies of the 5alpha-reductase enzyme genes (SRD5A1 on chromosome 5 and SRD5A2 on chromosome 2) using dimorphic intragenic restriction fragment length polymorphisms [15].
• CONCLUSION: These results suggest that polymorphisms of SRD5A1 and SRD5A2 genes may not be directly associated with the development of baldness or generation of different clinical phenotypes [1].
• Our results imply that these sequences may be either coding parts of yet unknown, active SRD5A1 genes, and/or of previously unidentified pseudogenes [16].
• Our research provide the first evidence for the existence of two new SRD5A1 related, previously unidentified sequences in the human genome [16].

Anatomical context of SRD5A1

• Regulation of HSD17B1 and SRD5A1 in lymphocytes [17].
• The activity of the type 2 isozyme of steroid 5 alpha-reductase is crucial for normal development of the external genitalia and prostate in human males [18].
• We previously described the cloning of rat and human cDNAs that encode steroid 5 alpha-reductase and their expression in oocytes and cultured cells [19].
• The enzyme steroid 5 alpha-reductase, via NADPH, catalyses the conversion of testosterone to dihydrotestosterone, which is required for the embryonic differentiation of the external male genitalia and the prostate [20].
• Thalamocortical terminals from MD in PFC are also of the SR type and form asymmetrical synaptic contacts predominantly with dendritic spines arising from the apical or basal dendrites of pyramidal cells whose somata reside in layers III, V and VI [21].

Associations of SRD5A1 with chemical compounds

• RESULTS: The sequence analysis of exon 3 of the SRD5A1 gene indicated an adenine-to-guanine change (ACA vs. ACG), both triplets encoding the amino acid residue threonine [2].
• In contrast, daily oral treatment with even a low 1 mg/kg/d dose of the dual SRD5A1 and SRD5A2 inhibitor, dutasteride, reduces both normal prostate and H tumor DHT content and weight in intact rats while elevating tissue testosterone [3].
• SRD5A1 expression was increased in the presence of 5alpha-DHT although no consistent changes were observed when the cells were treated with testosterone [17].
• Other steroids, including dexamethasone, progesterone, and 6-hydroxypregnanolone, produced no effects on expression of either HSD17B1 or SRD5A1 [17].
• These results suggest that functional genetic variants might exist in or around SRD5A1 that affect the activity of the 5alpha-reductase enzyme type 1 and influence androgen levels [22].

Other interactions of SRD5A1

• In contrast, AKR1C3, which shares 84% sequence identity, and 5alpha-reductase type I (SRD5A1) were minimally affected [23].
• We investigated 10 patients with elevated T/DHT ratios in whom mutations in the SRD5A2 and AR genes had been excluded to find out whether structural alterations of the SRD5A1 gene could contribute to their genital malformations [2].
• Treatment with 10 or 50 microM forskolin resulted in a 20-60% reduction of expression for HSD17B1 (encoding 17beta-HSD I) in T and B lymphoid cell lines and peripheral blood mononuclear cells, although such a change was not observed in the expression of SRD5A1 (encoding 5alpha-reductase I) [17].
• In contrast to P-450 3 and steroid 5 alpha-reductase, however, the elevation of P-450j protein was transient and was not accompanied by an increase in P-450j-associated hepatic microsomal aniline hydroxylase activity [24].
• Single-stranded conformation polymorphism analysis (SSCP) and DNA sequencing were performed after polymerase chain reaction amplification of each of the 5 exons of the SRD5A1 gene in both hyperandrogenic and control group (16 participants) [25].

Analytical, diagnostic and therapeutic context of SRD5A1

• EXPERIMENTAL DESIGN: Real-time PCR and enzymatic assays were used to determine the levels of SRD5A1 and SRD5A2 in normal versus malignant rat and human prostatic tissues [3].
• Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II [26].
• The SRD5A1 and SRD5A2 genes encoding the steroid 5 alpha-reductase type 1 and type 2 isoenzymes have been previously assigned by in situ hybridization to 5p15 and 2p23, respectively [27].
• The disposition of [14C]finasteride, a competitive inhibitor of steroid 5 alpha-reductase, was investigated after oral administration of 38.1 mg (18.4 microCi) of drug in six healthy volunteers [28].
• Inhibition of steroid 5 alpha-reductase activity by aliphatic fatty acids. Candidates for chemoprevention of prostate cancer [29].

References