Disease relevance of CYP11B1

• Mutations in the CYP11B1 gene cause steroid 11 beta-hydroxylase deficiency, a form of congenital adrenal hyperplasia characterized by signs of androgen excess and by hypertension [1].
• Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2 [2].
• Deletion hybrid genes, due to unequal crossing over between CYP11B1 (11beta-hydroxylase) and CYP11B2(aldosterone synthase) cause steroid 11beta-hydroxylase deficiency and congenital adrenal hyperplasia [3].
• Apparently the 11beta-hydroxylase deficiency and the adrenal hyperplasia are due to the lack of expression of this gene in the adrenal zona fasciculata/reticularis resulting from replacement of the CYP11B1 promoter and regulatory sequences by those of CYP11B2 [3].
• Steroid 11 beta-hydroxylase deficiency (11 beta OHD), an autosomal recessive hereditary disease, accounts for 5-8% of cases of congenital adrenal hyperplasia [4].

Psychiatry related information on CYP11B1

• The subjects were tested with the following instruments: Event Effect Scale, PTSS-10 Scale, FHI, Brief Eysenck's Personality Inventory, LEAIQ, GHQ-60, General Questionnaire for Accidents [5].

High impact information on CYP11B1

• Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase [6].
• This mutation is not normally present in CYP11B2 and thus appears to have arisen in CYP11B1 as a true point mutation rather than a gene conversion [7].
• Steroid 11 beta-hydroxylase (P450c11) deficiency (failure to convert 11-deoxycortisol to cortisol) causes less than 10% of cases of congenital adrenal hyperplasia in most populations, but it is relatively frequent in Jews of Moroccan origin [7].
• The mutant gene discovered in the glucocorticoid-suppressible variety (FHI) codes for an aldosterone biosynythetic enzyme normally controlled by angiotensin II, and now controlled by corticotropin [8].
• The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme [9].

Chemical compound and disease context of CYP11B1

• We have studied a patient with congenital adrenal hyperplasia and steroid 11beta-hydroxylase deficiency who was homozygous for a deletion of the CYP11B1 and CYP11B2 genes normally required for cortisol and aldosterone synthesis, respectively [3].
• The diagnosis of glucocorticoid-remediable aldosteronism had been traditionally made using the dexamethasone suppression test; however, recent studies have shown that several patients with primary aldosteronism and a positive dexamethasone suppression test do not have the chimeric CYP11B1/CYP11B2 gene [10].
• Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas [11].
• In stably transfected Y-1 cells, in which the herpes simplex virus thymidine kinase (HSV-TK) gene was driven by the CYP11B1 promoter with the P450scc enhancer element, HSV-TK expression and ganciclovir sensitivity were augmented by treatment with 8-bromo-cAMP, forskolin, and ACTH [12].

Biological context of CYP11B1

• P450c11 is encoded by the CYP11B1 gene which is located on chromosome 8q22 along with a homologous gene of unknown function, CYP11B2 [7].
• Cells transfected with hybrid cDNAs containing up to the first three exons of CYP11B1 synthesized aldosterone at levels near that of cells carrying normal CYP11B2, but cells transfected with hybrids containing the first five or more exons of CYP11B1 could not synthesize detectable amounts of aldosterone [2].
• The nucleotide sequences of CYP11B1 and B2 are 95% identical in coding regions and about 90% identical in introns [13].
• A partial cDNA clone encoding this enzyme has been previously isolated and the corresponding gene, CYP11B1, mapped to human chromosome 8q [13].
• We hypothesize that a molecular variant in CYP11B2 is in linkage disequilibrium (LD) with a key quantitative trait in CYP11B1 determining this phenotype [14].

Anatomical context of CYP11B1

• A related isozyme in the zona fasciculata, CYP11B1, is required for cortisol synthesis; this isozyme, which is normally expressed at much higher levels than CYP11B2, only has 11 beta-hydroxylase activity [2].
• When a cDNA corresponding to CYP11B1 of the 11 beta OHD patient was transfected into COS-7 cells, steroid 11 beta-hydroxylase activity was not detectable in mitochondria of the cells [4].
• Dissected neocortex and fetal zones were found to contain transcript for CYP11B1 using both the RNase protection assay and RT-PCR analysis [15].
• In contrast, P-45011 beta as expressed in the cultured cells exhibits steroid 11 beta-hydroxylase activity exclusively but fails to catalyze the synthesis of aldosterone and 18-oxocortisol [16].
• In the human fetal adrenal gland, CYP11B1/CYP11B2-IR was absent in the DZ but present in the TZ and FZ [17].

Associations of CYP11B1 with chemical compounds

• These data demonstrate that GSH is caused by expression of a gene that is regulated like CYP11B1 but that encodes a protein able to synthesize aldosterone [2].
• CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) are 93% identical mitochondrial enzymes that both catalyze 11beta-hydroxylation of steroid hormones [18].
• The effects of these compounds and also of 18-hydroxydeoxycorticosterone were tested in cells stably transfected with CYP11B1 and CYP11B2, the genes encoding 11beta-hydroxylase and aldosterone synthase, respectively [19].
• Metyrapone (IC50) of 1 microM) and 3-MeSO2-DDE (10 microM: 66 +/- 10% of control) were found to inhibit the apparent CYP11B1 activity [20].
• Ketoconazole inhibited all enzymes examined with the greatest effects on CYP11B1 (IC50) of 2.5 microM) [20].

Regulatory relationships of CYP11B1

• P-450C18 as expressed in COS-7 cells exhibits steroid 18-hydroxylase activity to catalyze the synthesis of aldosterone and 18-oxocortisol and exhibits steroid 11 beta-hydroxylase activity as well [16].
• Transcription of CYP11B1 also appeared to be regulated by steroidogenic factor-1 (SF-1) [21].
• The ability of LRH-1 to enhance transcription of the gene encoding human 11 beta- hydroxylase (hCYP11B1) was then examined using the H295R adrenal cell line [22].

Other interactions of CYP11B1

• The extra gene is a hybrid with 5' regulatory and coding regions corresponding to CYP11B1 and 3' coding regions from CYP11B2 [2].
• These disorders result from mutations in the CYP11B1 and CYP17 genes encoding the corresponding enzymes [23].
• Genes coding for enzymes involved in the later or final steps of steroid production (CYP11B1, CYP11B2, CYP19, 3beta-HSD1, 3beta-HSD2 and 17beta-HSD1) were up-regulated to various extents by most PCBs [24].
• Therefore, we used immunocytochemistry (ICC) to assess specific zonal localization and developmental regulation of CYP21A2 and CYP11B1/CYP11B2 in the human (13-24 weeks' gestation) and rhesus monkey (109 d-term) fetal adrenal gland [17].
• One polymorphism affects a putative steroidogenic factor-1 binding site (-344 T/C) in the 5'-regulatory region, whereas the other marker reflects replacement of the intron-2 from CYP11B2 with that from the neighboring gene encoding 11beta-hydroxylase (CYP11B1; wild-type/conversion) [25].

Analytical, diagnostic and therapeutic context of CYP11B1

• In all patients we amplified the CYP11B1 gene by PCR and sequenced exons 3-9 of CYP11B1 and a specific region (-138 to -284) of CYP11B2 promoter [10].
• Electrophoretic mobility shift assay demonstrated that SF-1 interacted with an element from both hCYP11B1 and hCYP11B2 [26].
• In situ hybridization showed that both CYP11B1 and the hybrid gene were expressed in all three zones of the cortex [27].
• The hybrid CYP11B gene was demonstrated to be expressed at higher levels than either CYP11B1 or CYP11B2 in the cortex of the adrenal by RT-PCR and Northern blot analysis [27].
• Thus, bilateral adrenalectomy in this patient allowed effective treatment of severe hypertension and helped in understanding the mechanisms and physiopathological consequences of two novel mutations of CYP11B1 [28].

References