China
Africa
Explore chapters and articles related to this topic
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
This gene contains 15 exons and is located on chromosome 14q32.1 (Lund et al. 1999). The CYP46A1 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, M. oryzae, A. thaliana, rice, and frog. The encoded protein contains 500 amino acids with a molecular weight of 56.8 kDa. CYP46A1 (also called cholesterol 24-hydroxylase) is predominantly expressed in the brain and converts cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol (Lund et al. 1999). The unique and conserved features of the enzyme implied that it plays important roles in the regulation of brain cholesterol metabolism. CYP46A1 resides in the ER. The LXRβ and CYP46A1 expression overlaps in the brain. 24-Hydroxycholesterol is a better substrate for CYP46A1 than cholesterol. The expression of CYP46A1 is inducible by epigenetic modifiers (Nunes et al. 2010; Shafaati et al. 2009). CYP46A is downregulated by the histone deacetylase inhibitor trichostatin A (Shafaati et al. 2009). In the 1.9-Å structure of CYP46A1 complexed with cholesterol 3-sulfate, the substrate is bound in the productive orientation and occupies the entire length of the banana-shaped hydrophobic active-site cavity (Mast et al. 2008). Structures of the co-complexes demonstrate that each drug binds in a single orientation to the active site of CYP46A1 with tranylcypromine, thioperamide, and voriconazole coordinating the heme iron via their nitrogen atoms and clotrimazole being at a 4-A distance from the heme iron (Mast et al. 2010). A unique helix B’-C loop insertion containing residues 116-120 contributes to positioning cholesterol for oxygenation catalyzed by CYP46A1. In the structure of CYP46A1 in complex with posaconazole, the long antifungal molecule coordinates the P450 heme iron with the nitrogen atom of its terminal azole ring and adopts a linear configuration occupying the whole length of the substrate access channel and extending beyond the protein surface (Mast et al. 2013). Numerous drug-protein interactions determine the submicromolar Kd of posaconazole for CYP46A1.
Standardizing and increasing the utility of lipidomics: a look to the next decade
Published in Expert Review of Proteomics, 2020
Yuqin Wang, Eylan Yutuc, William J Griffiths
24S-HC is generated from cholesterol by CYP46A1 expressed in neurons [121]. It acts as a transport molecule, removing excess cholesterol from brain [122]. Despite the comparatively mild phenotype of the Cyp46a1 knock-out mouse [123,124], CYP46A1 appears to be an essential enzyme in human as no inborn error of metabolism resulting from its deficiency has been reported and neither has an individual been found lacking in 24S-HC. Total (unesterified plus esterified) 24S-HC is a marker of neurodegeneration, patients with advanced multiple sclerosis have decreased plasma levels of 24S-HC, but patients in an early stage have increased levels [125]. This can be explained by acute episodes of demyelination causing transient increase in 24S-HC [126]. Similarly, patients with advanced Alzheimer’s disease (AD) have significantly reduced levels of plasma 24S-HC [127]. In both AD and multiple sclerosis, the reduced 24S-HC with advanced disease stage can be explained by the loss of CYP46A1 expressing neurons. This concept can also explain reduced plasma levels during the progression of Huntington’s disease [128]. With respect to Parkinson’s disease the prevailing data suggests that total 24S-HC increases in cerebrospinal fluid of patients with early Parkinson’s disease explained by release of cholesterol during cell death providing enhanced quantities of substrate for CYP46A1 [129]. Interestingly CYP46A1 gene therapy has been suggested as a treatment for Huntington’s disease [130], Alzheimer’s disease [131] and spinocerebellar ataxia [132].
Regulation of brain drug metabolizing enzymes and transporters by nuclear receptors
Published in Drug Metabolism Reviews, 2018
Dan Xu, Songqiang Huang, Hui Wang, Wen Xie
The phase I drug metabolizing enzymes mainly refer to various oxidoreductases and hydrolases, including the cytochrome P450 (CYP) superfamily, aldehyde dehydrogenase, ethanol dehydrogenase, and dihydropyrimidine dehydrogenase. The most abundantly expressed phase I enzymes are the P450s, many of which are highly expressed and inducible in the liver. In recent years, nearly two dozen of the P450s, including CYP1, CYP2, CYP3 family and CYP46A1, have been found in the brain. The expression, function and regulation of these brain P450s have gained increasing attention in research and drug development (Dutheil et al. 2009). Asai et al. (2018) showed that the expression of brain CYP2D4 was decreased in epileptic rats, which could change the pharmacokinetics and pharmacodynamics of various drugs in the brain. Kort et al. (2017) found that the use of CYP3A inhibitors induced the accumulation of multi-targeted receptor tyrosine kinase (RTK) inhibitor Ponatinib and its active metabolite N-Desmethyl Ponatinib in the brain. Mast et al. (2017) reported that the cholesterol-metabolizing CYP46A1 can be activated by the anti-HIV non-nucleoside reverse transcriptase inhibitor efavirenz, and the authors speculated that CYP46A1 can be a target to treat Alzheimer’s disease.
Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases
Published in Drug Metabolism Reviews, 2018
Cynthia Navarro-Mabarak, Rafael Camacho-Carranza, Jesús Javier Espinosa-Aguirre
Moreover, the induction of CYP46A1 activity has been recently tried with endogenous substrates and pharmacological agents (Table 2). l-Glutamate was the most effective endogenous CYP46A1 inducer, as it increased 3-fold the enzyme activity in vitro (Mast, Anderson et al. 2017). The antiretroviral medication Efavirenz (EFV) was the most effective synthetic CYP46A1 inducer. When it was tested in mice, EFV increased the cerebral cholesterol turnover, measured as cholesterol precursors and its hydroxylation products, at doses a hundred times lower than the prescribed for HIV patients (Mast et al. 2014). EFV’s therapeutic potential in AD was further demonstrated in 5XFAD mice (AD model of rapid amyloidogenesis), as a low dose of EFV improved cholesterol turnover and decreased amyloid burden, microglia activation, and APP levels (Mast, Saadane et al. 2017). Remarkably, EFV treatment increased the survival of male 5XFAD mice (given that females in all groups died less) at five and nine months of age. This is a very important fact, as it reflects the final effect of a CYP46A1-directed pharmacological treatment in the survival of an AD animal model for the first time.