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Role of Tandem Mass Spectrometry in Diagnosis and Management of Inborn Errors of Metabolism
Published in P. Mereena Luke, K. R. Dhanya, Didier Rouxel, Nandakumar Kalarikkal, Sabu Thomas, Advanced Studies in Experimental and Clinical Medicine, 2021
Kannan Vaidyanathan, Sandhya Gopalakrishnan
Matysik et al. have described a GC/MS method for the simultaneous determination of a variety of sterols (24-, 25-, 27-hydroxycholesterol; 7-ketocholesterol, lanosterol, lathosterol, 7-dehydrocholesterol, desmosterol, stigmasterol, sitosterol, and campesterol) in human plasma [41]. GC/MS was used to detect methylmalonicaciduria in a Chinese population. Over a 5 year period, 398 cases were detected, out of which 160 patients presented during neonatal period [42]. Cangemi et al. developed a GC/MS method for the determination of galactose-1-phosphate in RBC and suggest that this might be suitable in the treatment of classical galactosemia [43].
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
for conversion of both cholesterol and 27-hydroxycholesterol into bile acids, but does not mediate 7α-hydroxylation of pregnenolone and DHEA. Recently, another brain-enriched P450 7α-hydroxylase, called CYP7B, was identified and its cDNA cloned.123,124 This latter cDNA encodes a protein that catalyzes the 7α-hydroxylation of pregnenolone and DHEA in the brain, and also catalyzes 7α-hydroxylation of oxysterols. In addition to expression in the brain, CYP7B is found in rat liver and kidney, but is barely detectable in testis, ovary, and adrenal. Expression in the liver is dimorphic, with expression less in female rats than in male rats. CYP7b is widely expressed in the mouse brain and is regionally expressed in the hippocampus124; the highest concentrations are found in the corpus callosum. Among the P450s, CYP7b is most similar (39% at the amino acid sequence) to cholesterol 7α-hydroxylase (CYP7) and contains a postulated steroidogenic domain present in other steroid-metabolizing CYPs, but clearly represents a novel type of CYP. The formation of 7α-hydroxylated metabolites of pregnenolone and DHEA is low in prepubertal rats and increases fivefold in adults.135 It is unknown if brain expression of CYP7b parallels this enzymatic profile.
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
In liver, 7α-hydroxylation of cholesterols, mediated by CYP7A1 and 39A1, is the rate-limiting step of bile acid synthesis and metabolic elimination (Lathe 2002). In brain and other tissues, both sterols and some steroids including DHEA are prominently 7α-hydroxylated by CYP7B1. CYP39A1 is also known as oxysterol 7α-hydroxylase 2 (CYP7B1 is called oxysterol 7α-hydroxylase 1). The CYP39A1 gene contain 14 exons and are located on chromosome 6p12.3 (Li-Hawkins et al. 2000). The enzyme is an ER protein involved in the conversion of cholesterol to bile acids. It catalyzes the 7α-hydroxylation of 24-hydroxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol (Li-Hawkins et al. 2000). CYP39A1 is a microsomal CYP enzyme that has preference for 24-hydroxycholesterol and is expressed in the liver (Li-Hawkins et al. 2000). The levels of hepatic CYP39A1 mRNA do not change in response to dietary cholesterol, bile acids, or a bile acid-binding resin, unlike those encoding other sterol 7α-hydroxylases (CYP7A1 and 7B1). In mice, hepatic Cyp39a1 expression is sexually dimorphic (female > male), which is opposite that of Cyp7b1 (male > female) (Li-Hawkins et al. 2000). A recent genome-wide association study have identified 16 loci that are associated with levels of 19 sterols and 25-hydroxylated derivatives of vitamin D, including CYP39A1 (Stiles et al. 2014). Several pharmacogenetic studies have indicated that CYP39A1 mutations change the clinical response to anticancer drugs (Aslibekyan et al. 2014; ten Brink et al. 2013; Uchiyama et al. 2012). CYP39A1 genotypes are found to be associated with busulfan clearance in pediatric patients undergoing hematopoietic stem cell transplantation (ten Brink et al. 2013). Mutation of this gene is associated with methotrexate-induced ADRs in patients with rheumatoid arthritis (Aslibekyan et al. 2014). Interestingly, one CYP39A1 SNP (rs7761731, 972T>A → Asn324Lys) is found to be the only SNP significantly associated (P = 0.049; odds ratio = 9.0) with the incidence of grade 4 neutropenia induced by docetaxel in 42 Japanese patients with gynecological cancers such as ovarian cancer and endometrial cancer of the uterus (Uchiyama et al. 2012).
Botryosphaeran Attenuates Tumor Development and the Cancer Cachexia Syndrome in Walker-256 Tumor-Bearing Obese Rats and Improves the Metabolic and Hematological Profiles of These Rats
Published in Nutrition and Cancer, 2021
Patrícia K. Comiran, Mariana C. Ribeiro, John H. G. Silva, Kamila O. Martins, Izabella A. Santos, Ana Emilia F. Chiaradia, Amadeu Z. Silva, Robert F. H. Dekker, Aneli M. Barbosa-Dekker, Pâmela Alegranci, Eveline A. I. F. Queiroz
In the present study, we observed that all of the groups (CT, CTB, OT and OTB) presented hypercholesterolemia when compared with the range of reference values tabulated for healthy Wistar Rats (23). Literature studies have suggested that high cholesterol levels promote the proliferation of tumor cells by deregulating the homeostasis of cholesterol synthesis (40, 41). Oncogenic factors or mutations initiate activation of transcription factors such as SREBP (sterol regulatory-element binding proteins) and some proteins that import cholesterol into cells and, in sequence, transport them to the mitochondria by the START (Star-related lipid-transfer) protein STARD3 (StAR related lipid transfer domain containing 3) (40). This deregulation promotes an excess of cholesterol inside the mitochondria that can inhibit apoptosis, or can be metabolized to 27-hydroxycholesterol, which promotes the proliferation of tumor cells (40). The chemical 27-hydroxycholesterol induces the activation of NF-κβ transcription factor that contributes to the progression of breast and prostate cancer (41).
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
Another important oxysterol is 24S-hydroxycholesterol (24S-HC). In human, 24S-HC is the dominant diastereoisomer, although 24 R-HC is also present in plasma at much low levels Figure 5B. 24S-HC and 24R-HC are often unresolved in GC-MS and LC-MS experiments and ‘biological intelligence’ is invoked to characterize the oxysterol identified as the 24S-epimer. The geometrical similarity of 24S-HC, 24R-HC, 25-HC, (25R)26-hydroxycholesterol ((25R)26-HC, also known as 27-hydroxycholesterol) and of 22R-hydroxycholesterol, all of which are present in plasma at different levels makes their chromatographic separation challenging (see Figure 5 and also [109]). This challenge is accentuated in LC-MS/MS studies by the similarity of their MS/MS spectra which, in the absence of derivatization, are dominated by the loss of one or two molecules of water (see [117] and [118] for reference spectra). An advantage of the Girard P derivatization method used by Blanc et al [111], as developed by Griffiths and Wang [53,98,103,105,119,120], is that the derivatizing group which ‘charge-tags’ the analyte directs fragmentation resulting in MS3 spectra that are different for different oxysterol isomers. This in combination with enhanced solubility in reversed-phase solvents allows the determination of essentially all monohydroxycholesterol isomers Figure 5.
Further evidence for a continuous flux of bile acids into the brain: trapping of bile acids in subdural hematomas
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2020
Emanuele Porru, Erik Edström, Ahmed A. Saeed, Gösta Eggertsen, Anita Lövgren-Sandblom, Aldo Roda, Ingemar Björkhem
The 27-hydroxycholesterol and other metabolic precursors of bile acids were not evaluated in this study because of their conversion to cholic and chenodeoxycholic acid in brain has never been reported in brain. Nevertheless, the accumulation of other steroid compounds cannot be excluded, according to the mechanics described for bile acid and 7HOCA in subdural hematoma. Potential metabolic precursor of 7HOCA were previously evaluated [7] and levels of 3β-hydroxy-5-cholestenoic acid and 3β,7α-dihydroxy-5-cholestenoic acid were similar or higher than the plasma levels.