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Molecular effects and retinopathy induced by hydroxychloroquine during SARS-CoV-2 therapy: Role of CYP450 isoforms and epigenetic modulations.
Paniri, A, Hosseini, MM, Rasoulinejad, A, Akhavan-Niaki, H
European journal of pharmacology. 2020;:173454
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Abstract
Antimalaria drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) have been administered to several inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus, and infectious diseases such as acquired immune deficiency syndrome and influenza. Recently, several patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were given HCQ, and showed a discrepant response. HCQ inhibits SARS-CoV-2 cell entry, and inflammatory cascade by interfering with lysosomal and endosomal activities, and autophagy, impeding virus-membrane fusion, and inhibiting cytokine production resulted from inflammatory pathways activation. Despite ongoing administration of HCQ in a wide spectrum of disorders, there are some reports about several side effects, especially retinopathy in some patients treated with HCQ. Cytochrome P450 (CYP450) and its isoforms are the main metabolizers of HCQ and CQ. Pharmacokinetic properties of CYP enzymes are influenced by CYP polymorphism, non-coding RNAs, and epigenetic mechanisms such as DNA methylation, and histone acetylation. Accumulating evidence about side effects of HCQ in some patients raise the possibility that different response of patients to HCQ might be due to difference in their genome. Therefore, CYP450 genotyping especially for CYP2D6 might be helpful to refine HCQ dosage. Also, regular control of retina should be considered for patients under HCQ treatment. The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy.
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Substrate and enzyme trafficking as a means of regulating 1,25-dihydroxyvitamin D synthesis and action: the human innate immune response.
Adams, JS, Chen, H, Chun, R, Ren, S, Wu, S, Gacad, M, Nguyen, L, Ride, J, Liu, P, Modlin, R, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2007;:V20-4
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Abstract
Tissue availability of the active vitamin D metabolite, 1,25-dihydroxyvitamin D [1,25(OH)(2)D] is dependent on expression of the activating enzyme 1alpha-hydroxylase (CYP27b1) and its catabolic counterpart 24-hydroxylase (CYP24). The activity of these two enzymes is in turn controlled by factors including affinity of the serum vitamin D-binding protein (DBP) for 25-hydroxyvitamin D [25(OH)D]; the availability of enzyme cofactors; and the relative amount of hydroxylase gene product expressed. In recent years, it has become clear that directed trafficking of substrate and enzyme is also a pivotal component of the regulated process of hormone synthesis by both renal and extrarenal tissues expressing the CYP27b1 and CYP24 genes. Extracellular regulatory trafficking events are defined by the quantity of substrate 25(OH)D entering the circulatory pool. Entry into some target cells in vivo, such as the macrophage and proximal renal tubular epithelial cells, requires 25(OH)D binding to serum DBP, followed by recognition, internalization, and intracellular release. The "released" intracellular substrate is moved to specific intracellular destinations (i.e., the mitochondrial CYP enzymes and the vitamin D receptor [VDR]) by the hsc70 family of chaperone proteins. Synthesis of 1,25(OH)(2)D is also regulated by CYP24 and its metabolically inactive splice variant CYP24-SV. Finally, initiation of transcription of 1,25(OH)(2)D-regulated genes, such as the CYP24, requires movement of the CYP27b1 product, 1,25(OH)(2)D, to the VDR in the same cell for intracrine action or export to another cell for paracrine action. In either case, the 1,25(OH)(2)D ligand is required for the VDR to heterodimerize with the retinoid x receptor and compete away the dominant-negative acting, heterogeneous nuclear ribonucleoprotein (hnRNP)-related, vitamin D response element-binding proteins that inhibit hormone-directed transactivation of genes. In this review, we use vitamin D-directed events in the human innate immune response to Mycobacterium tuberculosis as a physiologically relevant model system in which to highlight the importance of these intracellular traffic patterns.