Disease relevance of CYP46A1

• Expression of human cytochrome P450 46A1 in Escherichia coli: effects of N- and C-terminal modifications [1].

Psychiatry related information on CYP46A1

• Variants of CYP46A1 may interact with age and APOE to influence CSF Abeta42 levels in Alzheimer's disease [2].
• CYP46 T/C polymorphism is not associated with Alzheimer's dementia in a population from Hungary [3].

High impact information on CYP46A1

• Conversion of cholesterol into 24S-hydroxycholesterol by the cholesterol 24-hydroxylase (CYP46A1) is the quantitatively most important mechanism [4].
• Cholesterol oxidation is mediated by the enzymes cholesterol 24-hydroxylase (CYP46A1) and cholesterol 27-hydroxylase (CYP27A1) [5].
• We analyzed an intronic T-->C substitution (rs 754203) of the cholesterol 24S-hydroxylase (CYP46) gene, encoding an enzyme acting on brain cholesterol turnover, which has been recently associated with an increased risk of AD, dependent or not on Apolipoprotein E (ApoE) genotype [6].
• Lack of association between the CYP46 gene polymorphism and Italian late-onset sporadic Alzheimer's disease [6].
• Intronic CYP46 polymorphism along with ApoE genotype in sporadic Alzheimer Disease: from risk factors to disease modulators [7].

Chemical compound and disease context of CYP46A1

• Association studies of cholesterol metabolism genes (CH25H, ABCA1 and CH24H) in Alzheimer's disease [8].
• Intron 2 (T/C) CYP46 Polymorphism Is Associated with Alzheimer's Disease in Chinese Patients [9].

Biological context of CYP46A1

• Recently, several independent studies have reported that a locus on chromosome 14q32.1, where a gene encoding a cholesterol degrading enzyme of the brain, called 24-hydroxylase (CYP46A1) is located, has been linked with AD [3].
• The distribution of CYP46 genotypes was significantly different in AD compared to controls (P<0.004), being CYP*C allele higher in AD patients ( P<0.002) [7].
• BACKGROUND: CYP46, the gene encoding cholesterol 24-hydroxylase, plays a key role in the hydroxylation of cholesterol and thereby mediates its removal from brain [10].
• The single nucleotide polymorphism (T/C) in intron 2 of CYP46 gene has been found to confer the risk for AD [3].
• CYP46A1 is an essential gene modulating cholesterol metabolism in the brain [11].

Anatomical context of CYP46A1

• Immunocytochemical studies show that CYP46A1 and CYP27A1 are expressed in neurons and some astrocytes in the normal brain, and CYP27A1 is present in oligodendrocytes [5].
• The water soluble 24(S)-hydroxysterol is the product of the CYP46A1, and elevated plasma and cerebrospinal fluid hydroxysterol concentrations have been found in AD, reflecting increased brain cholesterol turnover or cellular degradation, due to the neurodegenerative process [3].
• On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells [12].
• Further, in an autopsy confirmed subset of this cohort, the proposed CYP46 risk genotype was not associated with any increase in the brain levels of amyloid-beta40, amyloid-beta42 or in the levels of amyloid plaques and neurofibrillary tangles [13].

Associations of CYP46A1 with chemical compounds

• The frequency of the CYP46 C allele was similar (chi2=0.647, df=1, P=0.421, exact P=0.466, OR=0.845; 95% CI: 0.561-1.274) in both groups (CNT: 27%; 95% CI: 21.3-33.4; AD 30%; 95% CI: 25.0-36.3) [3].
• Two different members of the phosphoenolpyruvate carboxylase(PEPC)-encoding multigene family (clones lambda CP21 and lambda CP46) have been isolated from a Sorghum vulgare lambda EMBL4 genomic library [14].
• The use of the 3'-noncoding regions to probe Northern blots of RNA from roots, etiolated leaves and green leaves indicated that lambda CP21 and lambda CP46 encode the C3- and C4-type leaf PEPC isoforms, respectively [14].
• Our data indicate that the Intron 2 polymorphism of CYP46 does not affect the risk of AD in our sample [15].
• Many antineoplastic agents, on the other hand, inhibit the enzyme which include adriamycin, tamoxifen, alkyl-lysophospholipid, selenium, retinal and lipoidal amine CP-46, 665-1 [16].

Regulatory relationships of CYP46A1

• In the present study, these claims have been explored by the genotyping of previously associated markers in CYP46A1 in three independent northern European case-control series encompassing 1323 individuals and including approximately 400 patients with measurements of CSF Abeta42 and phospho-tau protein levels [2].

Other interactions of CYP46A1

• These findings provide direct evidence that CYP46 and ApoE polymorphisms synergically increase the risk for AD development, and influence on the rate of cognitive decline [7].
• APOE promoter, ACE1 and CYP46 polymorphisms and beta-amyloid in Alzheimer's disease [17].
• Exclusion of CYP46 and APOM as candidate genes for Alzheimer's disease in a French population [18].
• Preliminary evidence indicates that an intron 2 CYP46 T/C gene polymorphismis associated with increased brain Abeta load and higher risk of AD [19].
• Moreover, CYP46 AA-carriers were found to have increased levels of amyloid-beta and tau in brain and cerebrospinal fluid [13].

Analytical, diagnostic and therapeutic context of CYP46A1

• A case-control study was performed on 125 AD and 102 age- and gender-matched control subjects (CNT) from Hungary, to test the association of CYP46 T/C and apolipoprotein E (ApoE) gene polymorphisms in AD [3].
• A fragment of CYP46 intron 2 was amplified by PCR reaction and sequenced [20].

References