Disease relevance of Cyp17a1

• Here we delineate similarities and differences between the E. coli Fpr-Fld system and rat P450 reductase as electron donors to bovine 17alpha-hydroxylase/17,20-lyase P450 (P450c17) [1].
• Protein levels of P450c17 in Leydig cells and serum concentrations of progesterone and corticosterone 24 h after induction of sham sepsis or sepsis were not different [2].

High impact information on Cyp17a1

• Detection of P450c17-independent pathways for dehydroepiandrosterone (DHEA) biosynthesis in brain glial tumor cells [3].
• Likewise, the FeSO4-induced formation of D was not blocked by the P450c17 inhibitor, SU-10603 [3].
• Thus MA-10 cells, unlike untransformed Leydig cells, do not express detectable amounts of P450c17 mRNA or P450c17 activity [4].
• Since SF-1 mediates cAMP-induced transcriptional regulation of the rat P450c17 gene, phosphorylation of SF-1 via protein kinase A is likely to play a regulatory role in transcriptional activation [5].
• The orphan nuclear receptor steroidogenic factor-1 regulates the cyclic adenosine 3',5'-monophosphate-mediated transcriptional activation of rat cytochrome P450c17 (17 alpha-hydroxylase/c17-20 lyase) [5].

Chemical compound and disease context of Cyp17a1

• The hypothesis that induction of chronic peritoneal sepsis would produce depression of serum testosterone due to a decrease in Leydig cell steroidogenic acute regulatory (StAR) protein or P450c17 steroidogenic enzyme was tested [2].
• The function of recombinant cytochrome P450s in intact Escherichia coli cells: the 17 alpha-hydroxylation of progesterone and pregnenolone by P450c17 [6].

Biological context of Cyp17a1

• This study suggests that a protein that binds to an SF-1 like sequence regulates both basal and cAMP-stimulated rat P450c17 gene expression in rodent cells [7].
• A model is described in which the P450c17 active site is refractory towards ketoconazole when the intermediary steroid is retained and being processed at that site [8].
• In all samples of fetal testis, 3beta-HSD was detected on Day 14.5 p.c., and immunoexpression of P450c17 appeared one day later on Day 15.5 p.c. Thereafter, immunoexpression of both enzymes remained intense throughout gestation and postnatally [9].
• Ketoconazole inhibition of the bifunctional cytochrome P450c17 does not affect androgen formation from the endogenous lyase substrate. The catalytic site remains refractory in the course of intermediary hydroxyprogesterone processing [8].
• The human choriogonadotropin-induced degradation of cytochrome P450c17 in incubated decapsulated testes can not be correlated with a stimulation of lipid peroxidation, and it is partially inhibited by estradiol but completely abolished by androstenedione [10].

Anatomical context of Cyp17a1

• Cytochrome P450c17, 17 alpha-hydroxylase/17,20 lyase, is a key enzyme in the steroidogenic pathway leading to the production of corticosteroids and androgens from the adrenal gland and sex steroids from the gonads [7].
• We have investigated the developmental pattern of expression and activity of 17alpha-hydroxylase/C-17,20-lyase cytochrome P450 (cytochrome P450c17) in the liver, stomach, duodenum, and testis of rats from day 18 of pregnancy to adulthood [11].
• The presence of P450c17 in astrocytes and neurons was supported by the ability of these cells to metabolize pregnenolone to DHEA in a dose-dependent manner as determined by RIA [12].
• Western blot analyses allowed identification of a specific P450c17 protein in the SC and immunohistochemical studies localized P450c17 in neurones and glial cells [13].
• Here, we combined molecular, anatomical, cellular and neurochemical approaches to provide the first demonstration of the existence of P450c17 and bioactivity in adult rat spinal cord (SC) [13].

Associations of Cyp17a1 with chemical compounds

• Expression of cytochrome P450c17 and other steroid-converting enzymes in the rat kidney throughout the life-span [14].
• The following enzymes were revealed at all ages by radiochemical identification of the corresponding products: 5alpha-reductase, cytochromes P450c17 and P450c21, 3beta-hydroxysteroid dehydrogenase (HSD)/delta5-delta4 isomerase, and 17beta- and 20alpha-HSDs, catalyzing reductive reactions [14].
• These cells do not express P450c17, 17betaHSD, or P450arom or produce DHEA, T, or estrogen [15].
• Interestingly, cytochrome b5 was found to dramatically inhibit both P450 reductase- and Fpr-Fld-supported P450c17 progesterone 17alpha-hydroxylase activity while in contrast 17alpha-OH-pregnenolone lyase activity was stimulated by b5 [1].
• Pulse-chase experiments combined with HPLC and radioactive steroid detection showed that SC slices converted [3H]pregnenolone into [3H]DHEA, a conversion markedly reduced by ketoconazole, a P450c17 inhibitor [13].

Other interactions of Cyp17a1

• Neurons express P450scc, P450c17, 3betaHSD, and P450arom and produce P5, DHEA, A4, and estrogen, but do not express 17betaHSD or produce T [15].
• RT-PCR and in situ hybridization revealed that these changes were mirrored by reductions in P450c17 messenger RNA in testes from fetuses from treated mothers compared with control levels [16].
• Similar to the immunostaining for 3beta-HSD and P450c17, immunostaining for LH receptor remained strong throughout gestation and during the first 7 days of postnatal life [9].
• DBP, but not flutamide, reduced expression of the steroidogenic enzymes cytochrome P450 side chain cleavage, cytochrome P450c17, and steroidogenic acute regulatory protein [17].

Analytical, diagnostic and therapeutic context of Cyp17a1

• Cytochrome P450c17 mRNA and protein were demonstrated by Northern blotting and Western blotting analyses, respectively [14].
• P450c17 mRNA, assessed by Northern blotting, protein and catalytic activity all peaked in the kidney samples at 15 days of life and declined thereafter [14].
• Real-time RT-PCR revealed P450c17 gene expression in all SC segments [13].
• However, there was a consistent and striking reduction in the amount of P450c17 detected by immunocytochemistry in testes from the groups given the higher dose of DES or OP [16].
• Polymerase chain reaction amplification of the cDNA encoding steroid 17 alpha-hydroxylase (P450c17) demonstrated very low levels of this transcript and a shorter variant of still lower abundance in rat adrenals and brain [18].

References