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Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Giovanna Di Nardo, Gianfranco Gilardi
CYP27A1 was found not only to metabolize vitamin D3 into 25-hydroxyvitamin D3 (25-OH-D3) but also cholesterol into 27-hydroxycholesterol and 7-dehydrocholesterol (7-DHC) into two metabolites, 26/27-hydroxy-7-dehydrocholesterol and 25-hydroxy-7-dehydrocholesterol. Also in this case, a whole cells approach allowed high yield of bioconversion approaching 100% in 48 h for cholesterol turnover (Ehrhardt et al., 2016).
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
CYP27A1 (also called sterol 27-hydroxylase) is mainly expressed in the liver and located in mitochondria. CYP27A1 mRNA is also observed in macrophages (Gottfried et al. 2006), leukocytes (Shiga et al. 1999), skin fibroblasts (Garuti et al. 1997), kidney (Gascon-Barre et al. 2001), and the arterial wall (Shanahan et al. 2001). The enzyme catalyzes the 27-hydroxylation of cholesterol and 25-hydroxylation of vitamin D3 (Jones et al. 2014; Norlin and Wikvall 2007; Pikuleva 2006; Pikuleva et al. 1997; Tieu et al. 2012; Wikvall 2001). Bioactivation of cholesterol into bile acids is crucial for regulation of cholesterol homeostasis. The “classic” pathway of bile acid formation starts with a 7α-hydroxylation of cholesterol by CYP7A1 in the liver, while the “acidic” pathway starts with a hepatic or extrahepatic 27-hydroxylation by CYP27A1 (Norlin and Wikvall 2007). Formation of cholic acid requires insertion of a 12α-hydroxyl group catalyzed by CYP8B1. Oxysterols are precursors to bile acids, participate in cholesterol transport, and are known to affect the expression of several genes in cholesterol homeostasis. CYP27A1 is attached to the inner mitochondrial membrane and substrates appear to reach the active site through the membrane phase. The distance between the hydroxylation site and the end of the site chain is proportional to the regioselectivity of the enzyme (Dilworth et al. 1995).
The Cerebellar Ataxias and Hereditary Spastic Paraplegias
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Cholestanolosis (cerebrotendinous xanthomatosis) presents as a childhood-onset cerebellar ataxia with spasticity (which may be the prime feature), epilepsy, cognitive impairment, cataracts, neuropathy and xanthomas on tendons. Magnetic resonance scanning of the brain shows lesions of the dentate nuclei, brainstem and basal ganglia. The level of CSF protein is elevated and cholestanol levels are also increased as a result of an abnormality of bile salt synthesis; early treatment with chenodeoxycholic acid is partly effective. The condition is caused by mutations of the sterol 27-hydroxylase (CYP27A1) gene. Limited treatment is possible with chenodeoxycholic acid and pravastatin.
Early diagnosis for cerebrotendinous xanthomatosis with juvenile cataract and family history
Published in Ophthalmic Genetics, 2023
Nurşen Öncel Acır, Burcu Taskiran Kandeger
The CYP27A1 mutation encoding the enzyme involved in bile acid synthesis results in the shifting of cholesterol to the cholestanol pathway (3). Clinical problems are caused by an increase in cholestanol and bile alcohols in the blood, urine, and feces, which then cross the blood-brain barrier and accumulate in various organs (15). Although cholestanol levels increase significantly in this disease, plasma cholesterol levels remain normal. Despite deposits in multiple organs, early-onset juvenile cataracts, and symptoms such as recurrent diarrhea episodes, the presence of cerebrotendinous xanthomatosis frequently remains misdiagnosed for years. However, with an early diagnosis of the disease, the production and plasma levels of cholestanol and bile alcohols decrease following the initiation of oral chenodeoxycholic acid (6,16). Moreover, the neurological complications of the disease can be prevented or even reversed (16). At this point, the early detection of the condition and the timing of the administration of chenodeoxycholic acid are critical. For this reason, juvenile cataract, which is one of the first symptoms, the morphology of the cataract, and the patient’s family history are of vital importance.
Vitamin D: sources, physiological role, biokinetics, deficiency, therapeutic use, toxicity, and overview of analytical methods for detection of vitamin D and its metabolites
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Jiří Janoušek, Veronika Pilařová, Kateřina Macáková, Anderson Nomura, Jéssica Veiga-Matos, Diana Dias da Silva, Fernando Remião, Luciano Saso, Kateřina Malá-Ládová, Josef Malý, Lucie Nováková, Přemysl Mladěnka
Both dietary and endogenously formed vitamin D2/3 are two steps away from their active forms. The first activation step is the conversion of vitamin D2/3 to its 25-hydroxylated form, calcifediol, denoted 25(OH)D2/3, in the liver (Figure 4). There are many enzymes with 25-hydroxylase activity, but evidence indicates that microsomal cytochrome P450 2R1 (CYP2R1) is the principal vitamin D hydroxylase in humans. Mitochondrial CYP27A1 can also carry out this reaction but only in the case of vitamin D3 [119–122]. There is also a unique alternative activation pathway for vitamin D2 by hepatic 24-hydroxylase (CYP24A1) since formed 24(OH)D2 may undergo further activation to 1,24(OH)D2 in the kidney [123,124]. Contrarily, hydroxylation of biologically active 1,25(OH)2D3 in position 24 results in its deactivation, as mentioned below.
Impact of DNA methylation on ADME gene expression, drug disposition, and efficacy
Published in Drug Metabolism Reviews, 2022
Xu Hao, Yuanyuan Li, Jialu Bian, Ying Zhang, Shiyu He, Feng Yu, Yufei Feng, Lin Huang
Vitamin D is the basic medicine for the treatment of osteoporosis, and its preparations mainly include ordinary vitamin D and calcitriol. Vitamin D is metabolized to 25(OH)D in the liver by CYP2R1 and CYP27A1. Then, in the kidney and other tissues, 25(OH)D is activated to calcitriol. Both 25(OH)D and calcitriol are metabolically inactivated by CYP24A1(CYP24) (Zhou et al. 2014). Zhou et al. verified that the baseline DNA methylation levels at eight CpG sites of CYP2R1 were negatively associated with 12-month increases in serum 25(OH)D, and the baseline DNA methylation levels at two CpG sites of CYP24A1 were also negatively associated with vitamin D response variation (Zhou et al. 2014). Novakovic et al. revealed that CYP24A1 gene was methylated in human placenta, purified cytotrophoblasts, and primary and cultured chorionic villus sampling tissue. And CYP24A1 promoter methylation down-regulated gene expression and abolished vitamin D mediated feedback activation, which played an important role in maximizing active vitamin D bioavailability at the fetal-maternal interface (Novakovic et al. 2009). The above two studies found a consistent correlation between CYP24A1 promoter methylation and the effects of vitamin D. Wjst et al. reported that there seemed to be also a tendency for higher MRs of CYP27B1 with lower 25-OH-D3 serum values (Wjst et al. 2010).