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Effect of psychotropic drug treatment on sterol metabolism.
Korade Ž, Liu W, Warren EB, Armstrong K, Porter NA, Konradi C
(2017) Schizophr Res 187: 74-81
MeSH Terms: Adult, Animals, Antidepressive Agents, Antipsychotic Agents, Body Mass Index, Cholestadienols, Clozapine, Dehydrocholesterols, Female, Haloperidol, Humans, Lipid Metabolism, Male, Mental Disorders, Psychiatric Status Rating Scales, Random Allocation, Rats, Sprague-Dawley, Weight Gain
Show Abstract · Added April 6, 2017
Cholesterol metabolism is vital for brain function. Previous work in cultured cells has shown that a number of psychotropic drugs inhibit the activity of 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the final steps in cholesterol biosynthesis. This leads to the accumulation of 7-dehydrocholesterol (7DHC), a molecule that gives rise to oxysterols, vitamin D, and atypical neurosteroids. We examined levels of cholesterol and the cholesterol precursors desmosterol, lanosterol, 7DHC and its isomer 8-dehydrocholesterol (8DHC), in blood samples of 123 psychiatric patients on various antipsychotic and antidepressant drugs, and 85 healthy controls, to see if the observations in cell lines hold true for patients as well. Three drugs, aripiprazole, haloperidol and trazodone increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, did not. Studies in rat brain verified that haloperidol dose-dependently increased 7DHC and 8DHC levels, while clozapine had no effect. We conclude that further studies should investigate the role of 7DHC and 8DHC metabolites, such as oxysterols, vitamin D, and atypical neurosteroids, in the deleterious and therapeutic effects of psychotropic drugs. Finally, we recommend that drugs that increase 7DHC levels should not be prescribed during pregnancy, as children born with DHCR7 deficiency have multiple congenital malformations.
Copyright © 2017 Elsevier B.V. All rights reserved.
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18 MeSH Terms
Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design.
Hargrove TY, Friggeri L, Wawrzak Z, Sivakumaran S, Yazlovitskaya EM, Hiebert SW, Guengerich FP, Waterman MR, Lepesheva GI
(2016) J Lipid Res 57: 1552-63
MeSH Terms: 14-alpha Demethylase Inhibitors, Antifungal Agents, Antineoplastic Agents, Antiprotozoal Agents, Catalytic Domain, Cell Line, Tumor, Cholestadienols, Crystallography, X-Ray, Drug Design, Drug Screening Assays, Antitumor, Humans, Hydrogen Bonding, Lanosterol, Models, Molecular, Protein Binding, Protein Conformation, alpha-Helical, Sterol 14-Demethylase
Show Abstract · Added April 6, 2017
Rapidly multiplying cancer cells synthesize greater amounts of cholesterol to build their membranes. Cholesterol-lowering drugs (statins) are currently in clinical trials for anticancer chemotherapy. However, given at higher doses, statins cause serious side effects by inhibiting the formation of other biologically important molecules derived from mevalonate. Sterol 14α-demethylase (CYP51), which acts 10 steps downstream, is potentially a more specific drug target because this portion of the pathway is fully committed to cholesterol production. However, screening a variety of commercial and experimental inhibitors of microbial CYP51 orthologs revealed that most of them (including all clinical antifungals) weakly inhibit human CYP51 activity, even if they display high apparent spectral binding affinity. Only one relatively potent compound, (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide (VFV), was identified. VFV has been further tested in cellular experiments and found to decrease proliferation of different cancer cell types. The crystal structures of human CYP51-VFV complexes (2.0 and 2.5 Å) both display a 2:1 inhibitor/enzyme stoichiometry, provide molecular insights regarding a broader substrate profile, faster catalysis, and weaker susceptibility of human CYP51 to inhibition, and outline directions for the development of more potent inhibitors.
Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.
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17 MeSH Terms
CYP51 from Trypanosoma brucei is obtusifoliol-specific.
Lepesheva GI, Nes WD, Zhou W, Hill GC, Waterman MR
(2004) Biochemistry 43: 10789-99
MeSH Terms: Amino Acid Sequence, Animals, Cholestadienols, Cloning, Molecular, Cytochrome P-450 Enzyme System, Isoenzymes, Oxidoreductases, Protozoan Proteins, Rats, Sequence Alignment, Sterol 14-Demethylase, Substrate Specificity, Trypanosoma brucei brucei
Show Abstract · Added February 12, 2015
New isoforms of CYP51 (sterol 14alpha-demethylase), an essential enzyme in sterol biosynthesis and primary target of azole antimycotic drugs, are found in pathogenic protists, Trypanosoma brucei(TB), T. vivax, T. cruzi, and Leishmania major. The sequences share approximately 80% amino acid identity and are approximately 25% identical to sterol 14alpha-demethylases from other biological kingdoms. Differences of residues conserved throughout the rest of the CYP51 family that align with the BC-loop and helices F and G of CYP51 from Mycobacterium tuberculosis (MT)) imply possible alterations in the topology of the active site cavity of the protozoan enzymes. CYP51 and cytochrome P450 reductase (CPR) from TB were cloned, expressed in Escherichia coli, and purified. The P450 has normal spectral features (including absolute absorbance, carbon monoxide, and ligand binding spectra), is efficiently reduced by TB and rat CPR but demonstrates altered specificity in comparison with human CYP51 toward three tested azole inhibitors, and contrary to the human, Candida albicans, and MT isoforms, reveals profound substrate preference toward obtusifoliol (turnover 5.6 min(-1)). It weakly interacts with the other known CYP51 substrates; slow lanosterol conversion predominantly produces the 14alpha-carboxyaldehyde intermediate. Although obtusifoliol specificity is typical for plant isoforms of CYP51, the set of sterol biosynthetic enzymes in the protozoan genomes together with available information about sterol composition of kinetoplastid cells suggest that the substrate preference of TBCYP51 may reflect a novel sterol biosynthetic pathway in Trypanosomatidae.
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13 MeSH Terms