Disease relevance of Cyp11a1

• The results revealed a decreased expression of mRNA of P450scc enzyme and StAR during nephrosis, and eventhough they increased after gonadotropins treatment, they did not conduce to a normal cycling rat period or fertility recovery [1].
• C6 rat glioma tumor cells in culture biosynthesize both pregnenolone (P) and D. They possess the mRNA, protein, and side-chain cleavage activity of P450scc [2].
• We found no effect of either drug on P450scc in intact human choriocarcinoma JEG-3 cells [3].
• Testicular cholesterol side-chain cleavage enzyme (CSCCE) and delta5-3beta-hydroxysteroid dehydrogenase (delta5-3beta-HSD) activities were assessed 12 hours and 2, 4, 8, 16, and 32 days after surgical induction of bilateral cryptorchidism in adult rats [4].
• In conclusion, this study demonstrates that the expression of P450scc and StAR protein are highly impaired during nephrotic syndrome [5].

Psychiatry related information on Cyp11a1

• In contrast, non-selective sleep disturbance, resulting in the partial reductions of non-REM and REM sleep, tended to increase both StAR and P450scc mRNA levels without any statistical significance [6].

High impact information on Cyp11a1

• In rat adrenal cells, etomidate produced a concentration-dependent blockade of the two mitochondrial cytochrome P-450-dependent enzymes, cholesterol-side-chain cleavage enzyme, and 11 beta-hydroxylase, without evident inhibition of the microsomal enzymes in the glucocorticoid pathway [7].
• The induction of progesterone secretion is observed only after approximately 24 h and closely follows the delayed but quantitatively dramatic induction of the mitochondrial cytochrome P450scc which catalyzes the first step in steroid hormone biosynthesis [8].
• Induction and mitochondrial localization of cytochrome P450scc system enzymes in normal and transformed ovarian granulosa cells [8].
• Taken together with our previous finding of a P450scc-containing neuronal system for pregnenolone synthesis, these results imply that 17beta-estradiol is synthesized by P45017alpha and P450 aromatase localized in hippocampal neurons from endogenous cholesterol [9].
• A pathway for the metabolism of vitamin D3: unique hydroxylated metabolites formed during catalysis with cytochrome P450scc (CYP11A1) [10].

Chemical compound and disease context of Cyp11a1

• This study demonstrates that the mechanism by which ovarian steroid biosynthesis is altered during acute nephrosis involves damage at the P450scc and StAR mRNA synthesis and processing [1].
• P450scc was transcriptionally regulated in Y-1, MA-10, and C6 glioma cells, but not in GC or GT1-7 cells [11].
• In Experiment 1, naturally-receptive rats received bilateral VTA infusions of a P450scc inhibitor, digitoxin (1 microg/side); a 5alpha-reductase inhibitor, finasteride (10 microg/side); digitoxin (1 microg/side)+finasteride (10 microg/side); or vehicle and were tested 3 h later for lordosis [12].
• In contrast, the expression of P450scc, a mitochondrial protein, is decreased by Cm but enhanced by ethanol, a powerful elicitor of heat shock response in E. coli [13].

Biological context of Cyp11a1

• Transcriptional regulation of P450scc gene expression in the embryonic rodent nervous system [14].
• A crucial transcriptional regulatory region of the rat P450scc gene is at -130/-94 [14].
• We conclude that this cDNA is specific for the rat gene coding for cholesterol side-chain cleavage enzyme (P-450scc) by virtue of nucleotide sequence homology to the bovine and human P-450scc cDNA sequences [15].
• The 5'-UTR sequence of renal P450scc cDNA exactly matched the contiguous upstream untranslated region of the gene, suggesting that alternative splicing was not involved in the synthesis of this transcript [16].
• Based on NMR analysis and known properties of P450scc we propose that hydroxylation of vitamin D3 by P450scc occurs sequentially and stereospecifically with initial formation of 20(S)-hydroxyvitamin D3 [17].

Anatomical context of Cyp11a1

• Transcription of the P450scc gene in the adrenals and gonads requires steroidogenic factor-1, which is not expressed in the nervous system cells that express P450scc [14].
• Rat cholesterol side-chain cleavage enzyme (P-450scc): use of a cDNA probe to study the hormonal regulation of P-450scc mRNA levels in ovarian granulosa cells [15].
• Immunohistochemistry showed clear reductions of StAR, PBR, P450scc and PPARgamma protein levels in fetal Leydig cells, indicating that DEHP affects regulation of certain steps in cholesterol transport and steroid synthesis [18].
• We conclude that purified P450scc in a reconstituted system or P450scc in adrenal mitochondria can add one hydroxyl group to vitamin D3 with subsequent hydroxylation being observed for reconstituted enzyme but not for adrenal mitochondria [17].
• It therefore appears that non-P450scc enzymes present in the adrenal cortex to some extent contribute to metabolism of vitamin D3 [17].

Associations of Cyp11a1 with chemical compounds

• Ku colocalized with P450scc in several regions of the nervous system, but its overexpression in C6 cells did not augment transcription from a -130/-94 Luciferase construct [14].
• In the alcohol vapor models, both regimens of the drug also significantly depressed StAR and PBR protein concentrations, blunted the T response to hCG, and did not alter P450scc [19].
• The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism [17].
• P450scc did not metabolize 25-hydroxyvitamin D3, indicating that modification of C25 protected it against P450scc action [17].
• P450c11 converts deoxycorticosterone to corticosterone and aldosterone, and P450scc converts cholesterol to pregnenolone [20].

Physical interactions of Cyp11a1

• Thus, we have demonstrated, for the first time, the presence of PBR and StAR in the pregnant rat CL and that the coordinated suppression of these proteins involved in the mitochondrial cholesterol transport along with P450 scc by GnRH-Ag leads to reduced ovarian steroidogenesis [21].

Regulatory relationships of Cyp11a1

• Interestingly, IGF-I alone induced a 2-fold increase in P450scc [22].
• IFNgamma also reduced hCG-stimulated P450scc mRNA levels by 69% [23].
• In addition, lindane suppressed the FSH and TGF beta1-stimulated increases in progesterone production and the levels of P450scc enzyme and StAR protein [24].

Other interactions of Cyp11a1

• Rats (Day 3 pregnant) received an injection of streptozotocin (STZ, 60 mg/kg; i.v.) to induce a diabetic state; P450scc, 3 beta-HSD, and SCP2 were examined by Western and Northern blot analysis in ovarian tissue 12 days after injection of STZ (diabetic rats, n = 12) or vehicle (nondiabetic rats, n = 12) [25].
• GnRH-Ag also reduced, in the CL, the PBR protein/ligand binding, the StAR protein and P450 scc protein and its activity as early as 8 h after the treatment and they remained low compared with those in corresponding sham controls [21].
• Neurons express P450scc, P450c17, 3betaHSD, and P450arom and produce P5, DHEA, A4, and estrogen, but do not express 17betaHSD or produce T [26].
• Few changes were observed in the adrenal protein contents of cholesterol side-chain cleavage cytochrome P450 (P450scc), cytochrome P450 11beta-hydroxylase (P450C11), cytochrome P450 21-hydroxylase (P450C21), and 3beta-hydroxysteroid dehydrogenase (3betaHSD) [27].
• The expression of mRNA for cytochrome P450scc (converts cholesterol to pregnenolone), 3beta-hydroxysteroid dehydrogenase (converts pregnenolone to progesterone), and the progesterone receptor were detected and markedly induced during peak myelin formation in the cocultures [28].

Analytical, diagnostic and therapeutic context of Cyp11a1

• Positive immunodetections of cytochrome P450scc were found in renal cortical distal tubules and the results were confirmed by Western blotting analysis [16].
• Immunoblotting confirmed the presence of relatively high levels of cytochrome P-450 cholesterol side-chain-cleavage enzyme in C6-2B cell mitochondria [29].
• P450scc mRNA was unchanged after unilateral adrenalectomy and increased with ACTH infusion [30].
• To investigate these problems, in situ hybridization and immunocytochemistry were used to examine the ontogeny of expression of both the P450 side-chain cleavage (P450scc) and adrenodoxin genes during rat development [31].
• At various times, cytoplasmic mRNA was extracted from the TIC, and P450scc, 3 beta-HSD and P450(17 alpha) mRNA were measured by specific assays, using RT-PCR [32].

References