Disease relevance of Cyp11b@

• This observation suggests that glucocorticoid-remediable hyperaldosteronism could also be due to point mutations located in the CYP11B1 sequence [1].
• Structure/function relationship of CYP11B1 associated with Dahl's salt-resistant rats--expression of rat CYP11B1 and CYP11B2 in Escherichia coli [2].

High impact information on Cyp11b@

• The CYP11B1 gene, which encodes steroid 11 beta-monooxygenase, which is responsible for the synthesis of cortisol and corticosterone, the major glucocorticoids in mammals, is expressed specifically in the zona fasciculata of the adrenal cortex [3].
• One of these (CYP11B1) encodes P450c11 beta, which is the steroid 11 beta-hydroxylase found solely in the adrenal zona fasciculata/reticularis, and is responsible for the conversion of 11-deoxycorticosterone to corticosterone [4].
• In the nucleotide sequences, CYP11B1, -B3, and -B4 showed 95-96 and 93-100% identities in the coding and 0.5-kilobase 5'-flanking regions, respectively [5].
• Aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) catalyze the production of aldosterone and corticosterone, respectively, in the rat adrenal cortex [6].
• We have developed a highly sensitive QRT-PCR method for the measurement of CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) mRNAs to study their expression in the rat brain in response to dietary sodium manipulation and angiotensin (Ang)II infusion [7].

Biological context of Cyp11b@

• We have created stably transfected cell lines using the Leydig tumor cell line MA-10 with CYP11B1 and CYP11B2 cDNA-containing plasmids which have a selectable gene to confer resistance to geneticin [8].
• CYP11B1 and CYP11B2 genes were highly homologous (88.5%) in their nucleotide sequences of the amino acid coding regions [9].
• A putative Ad4 site, a cis-acting element present in the promoter regions of all the steroidogenic P-450s so far reported [Morohashi, K., Honda, S., Inomata, Y., Handa, H., Omura, T. (1992) J. Biol. Chem. 267, 17913-17919], was found in the promoter regions of both CYP11B1 and CYP11B2 [10].
• Dahl's salt-resistant normotensive rats (DR rats) have been previously reported to express cytochrome P-450 (CYP11B1) containing five missense mutations [Matsukawa, N., Nonaka, Y., Higaki, J., Nagano, M., Mikami H., Ogihara, T. & Okamoto, M. (1993) J. Biol. Chem. 268, 9117-9121] [2].
• CYP11B1 is found in all the zones of the gland and catalyzes a single hydroxylation of deoxycorticosterone (DOC) in the 11 beta- or the 18-position [11].

Anatomical context of Cyp11b@

• CYP11B2 and CYP11B1 expression was measured in RNA from adrenal gland and discrete brain regions using real-time QRT-PCR [7].
• Glucocorticoids and mineralocorticoids are synthesized in the adrenal cortex through the action of two different cytochrome 11 beta-hydroxylases, CYP11B1 (11 beta-hydroxylase) and CYP11B2 (aldosterone synthase) which are distributed in the zona fasciculata and glomerulosa, respectively [8].
• As shown by an immunoblot analysis, the adrenal capsule portions (mainly zona glomerulosa) of the rats kept on the low Na diet for 14d expressed significantly higher levels of both CYP11B2 and CYP11B1, and contained a significantly higher amount of CYP11B2 than those from the rats fed by normal diet [9].
• In vitro, only CYP11B1 activity was detectable and responsive to ACTH treatment in zona glomerulosa cells cultured at a potassium concentration of 6.4 mmol/l. Aldosterone biosynthetic activity and mRNA encoding CYP11B2 could be detected only after at least 1 day of exposure to a high extracellular potassium concentration (> or = 12 mmol/l) [11].

Associations of Cyp11b@ with chemical compounds

• CYP11B2 transfected cells (but not the CYP11B1 transfected cells) transform 18-OH-DOC into 18-OH-corticosterone, but can not convert 18-OH-DOC into aldosterone [8].
• The effects of a calcium channel blocker (nifedipine) and a protein synthesis inhibitor (cycloheximide) on the induction of four steroidogenic cytochromes P450 (CYP11B2, CYP11B1, CYP11A1, and CYP21A1) by an elevated extracellular potassium concentration were studied in cultured rat zona glomerulosa cells [12].
• Steroid 11beta-hydroxylase (11beta-OHase) activity observed with DR-CYP11B1 was similar to that of wild-type CYP11B1, while 18-hydroxylase (18-OHase) activity of DR-CYP11B1 was lower than that of wild-type CYP11B1 [2].
• The effects of corticotropin on mRNA levels of the jun and fos family genes as well as transcription of CYP11B1 in Y1 cells were mimicked by treatment of the cells with dibutyryl cAMP [13].
• In all zones of the adrenal cortex, the CYP11B1 mRNA level was decreased upon dexamethasone treatment [14].

Physical interactions of Cyp11b@

• Subsequent extractions with chloroform and methanol showed inhibition of substrate binding and conversion with hydrophobic compounds exhibiting a greater inhibitory effect on deoxycorticosterone binding to CYP11B1 (30%) and on progesterone binding to CYP21 (50%) [15].

Other interactions of Cyp11b@

• In vitro, the CYP11B2 (aldosterone synthase) of the glomerulosa can and does utilise as substrates products arising from CYP11B1 (11beta-hydroxylase) activity in fasciculata cells [16].
• Brain CYP11B1 mRNA levels were 10- to 1000-fold higher than CYP11B2 but were unaffected by dietary sodium or AngII [7].
• Water extracts showed inhibition of substrate binding to cytochrome P450 21-hydroxylase (CYP21) by 38% and cytochrome P450 11beta-hydroxylase (CYP11B1) by 60% [15].

Analytical, diagnostic and therapeutic context of Cyp11b@

• Although CYP11B3 has similar gene structure and great homology to the CYP11B1 and -B2 genes, the CYP11B3 mRNA was not originally detected by reverse transcription-polymerase chain reaction (RT-PCR) and has only recently been cloned and detected from neonatal rat adrenals [17].
• Regulation of aldosterone synthase cytochrome P450 (CYP11B2) and 11 beta-hydroxylase cytochrome P450 (CYP11B1) expression in rat adrenal zona glomerulosa cells by low sodium diet and angiotensin II receptor antagonists [9].
• The effects of the extracellular potassium concentration on the expression of four steroidogenic cytochromes P-450 (CYP11B2, CYP11B1, CYP11A1, and CYP21A1) in cultured rat adrenal zona glomerulosa cells were studied by Northern blot analysis [18].

References