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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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Cytochrome P450 enzymes: A driving force of plant diterpene diversity.
Bathe, U, Tissier, A
Phytochemistry. 2019;:149-162
Abstract
In plant terpene biosynthesis, oxidation of the hydrocarbon backbone produced by terpene synthases is typically carried out by cytochrome P450 oxygenases (CYPs). The modifications introduced by CYPs include hydroxylations, sequential oxidations at one position and ring rearrangements and closures. These reactions significantly expand the structural diversity of terpenoids, but also provide anchoring points for further decorations by various transferases. In recent years, there has been a significant increase in reports of CYPs involved in plant terpene pathways. Plant diterpenes represent an important class of metabolites that includes hormones and a number of industrially relevant compounds such as pharmaceutical, aroma or food ingredients. In this review, we provide a comprehensive survey on CYPs reported to be involved in plant diterpene biosynthesis to date. A phylogenetic analysis showed that only few CYP clans are represented in diterpene biosynthesis, namely CYP71, CYP85 and CYP72. Remarkably few CYP families and subfamilies within those clans are involved, indicating specific expansion of these clades in plant diterpene biosynthesis. Nonetheless, the evolutionary trajectory of CYPs of specialized diterpene biosynthesis is diverse. Some are recently derived from gibberellin biosynthesis, while others have a more ancient history with recent expansions in specific plant families. Among diterpenoids, labdane-related diterpenoids represent a dominant class. The availability of CYPs from diverse plant species able to catalyze oxidations in specific regions of the labdane-related backbones provides opportunities for combinatorial biosynthesis to produce novel diterpene compounds that can be screened for biological activities of interest.
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Cytochrome P450: Polymorphisms and Roles in Cancer, Diabetes and Atherosclerosis.
Elfaki, I, Mir, R, Almutairi, FM, Duhier, FMA
Asian Pacific journal of cancer prevention : APJCP. 2018;(8):2057-2070
Abstract
Cytochromes P450s (CYPs) constitute a superfamily of enzymes that catalyze the metabolism of drugs and other substances. Endogenous substrates of CYPs include eicosanoids, estradiol, arachidonic acids, cholesterol, vitamin D and neurotransmitters. Exogenous substrates of CYPs include the polycyclic aromatic hydrocarbons and about 80% of currently used drugs. Some isoforms can activate procarcinogens to ultimate carcinogens. Genetic polymorphisms of CYPs may affect the enzyme catalytic activity and have been reported among different populations to be associated with various diseases and adverse drug reactions. With regard of drug metabolism, phenotypes for CYP polymorphism range from ultrarapid to poor metabolizers. In this review, we discuss some of the most clinically important CYPs isoforms (CYP2D6, CYP2A6, CYP2C19, CYP2C9, CYP1B1 and CYP1A2) with respect to gene polymorphisms and drug metabolism. Moreover, we review the role of CYPs in renal, lung, breast and prostate cancers and also discuss their significance for atherosclerosis and type 2 diabetes mellitus.
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The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo.
Sychev, DA, Ashraf, GM, Svistunov, AA, Maksimov, ML, Tarasov, VV, Chubarev, VN, Otdelenov, VA, Denisenko, NP, Barreto, GE, Aliev, G
Drug design, development and therapy. 2018;:1147-1156
Abstract
Cytochrome (CYP) 450 isoenzymes are the basic enzymes involved in Phase I biotransformation. The most important role in biotransformation belongs to CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2. Inhibition and induction of CYP isoenzymes caused by drugs are important and clinically relevant pharmacokinetic mechanisms of drug interaction. Investigation of the activity of CYP isoenzymes by using phenotyping methods (such as the determination of the concentration of specific substrates and metabolites in biological fluids) during drug administration provides the prediction of negative side effects caused by drug interaction. In clinical practice, the process of phenotyping of CYP isoenzymes and some endogenous substrates in the ratio of cortisol to 6β-hydroxycortisol in urine for the evaluation of CYP3A4 activity has been deemed to be a quite promising, safe and minimally invasive method for patients nowadays.
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Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: case report and literature review.
Bai, Y, Li, J, Wang, X
Journal of ovarian research. 2017;(1):16
Abstract
BACKGROUND Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease exhibiting a variety of clinical manifestations. It can be difficult to differentiate with other diseases such as 21-hydroxylase deficiency (21-OHD), polycystic ovary syndrome (PCOS) and Antley-Bixler syndrome (ABS). Nearly 100 cases of PORD have been reported worldwide. However, the genetic characters and clinical management are still unclear, especially in China. CASE PRESENTATION In this study, we report a 27-year-old female Chinese patient who first presented with amenorrhea and recurrence of large ovary cyst. She was misdiagnosed with PCOS and non-classical 21-OHD due to ovary cysts and elevated 17-hydroxy-progesterone. The patient's complaining of a mild difficulty of bending the metacarpophalangeal joints reminded us to consider PORD, which usually presents with skeletal deformities and sexual dysfunction. The diagnosis of PORD was confirmed by genetic analyses, which showed the patient harboring a homozygous missense mutation in the POR gene (R457H) and her parents carrying the heterozygous mutation. The patient was treated with low-dose corticosteroids and estrogen/progesterone sequential therapy, and her ovarian cyst gradually reduced with regular menstruation in the follow-up. Moreover, the clinical and genetic characteristics of 104 previously reported PORD cases were also summarized and analyzed. CONCLUSIONS PORD is a very rare disease which can be easily misdiagnosed in mild cases. Clinicians should keep in mind of this disease in patients with sexual dysfunction, especially combined with special skeletal deformities. Our data could provide a consciously understanding of this disease for clinic practicers. Low-dose corticosteroids combined with estrogen/progesterone sequential therapy will be effective in PORD patients with recurrence of large ovary cyst. The fact that the reported PORD patients in China carrying an identical variant R457H in POR gene also give us a viewpoint that R457H mutation in POR gene maybe important in causing PORD in Chinese as same as in Japanese.
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Cardiovascular Pharmacogenomics--Implications for Patients With CKD.
Cavallari, LH, Mason, DL
Advances in chronic kidney disease. 2016;(2):82-90
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Abstract
CKD is an independent risk factor for cardiovascular disease (CVD). Thus, patients with CKD often require treatment with cardiovascular drugs, such as antiplatelet, antihypertensive, anticoagulant, and lipid-lowering agents. There is significant interpatient variability in response to cardiovascular therapies, which contributes to risk for treatment failure or adverse drug effects. Pharmacogenomics offers the potential to optimize cardiovascular pharmacotherapy and improve outcomes in patients with CVD, although data in patients with concomitant CKD are limited. The drugs with the most pharmacogenomic evidence are warfarin, clopidogrel, and statins. There are also accumulating data for genetic contributions to β-blocker response. Guidelines are now available to assist with applying pharmacogenetic test results to optimize warfarin dosing, selection of antiplatelet therapy after percutaneous coronary intervention, and prediction of risk for statin-induced myopathy. Clinical data, such as age, body size, and kidney function have long been used to optimize drug prescribing. An increasing number of institutions are also implementing genetic testing to be considered in the context of important clinical factors to further personalize drug therapy for patients with CVD.
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A Physiologic Approach to the Pharmacogenomics of Hypertension.
Eadon, MT, Chapman, AB
Advances in chronic kidney disease. 2016;(2):91-105
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Abstract
Hypertension is a multifactorial condition with diverse physiological systems contributing to its pathogenesis. Individuals exhibit significant variation in their response to antihypertensive agents. Traditional markers, such as age, gender, diet, plasma renin level, and ethnicity, aid in drug selection. However, this review explores the contribution of genetics to facilitate antihypertensive agent selection and predict treatment efficacy. The findings, reproducibility, and limitations of published studies are examined, with emphasis placed on candidate genetic variants affecting drug metabolism, the renin-angiotensin system, adrenergic signalling, and renal sodium reabsorption. Single-nucleotide polymorphisms identified and replicated in unbiased genome-wide association studies of hypertension treatment are reviewed to illustrate the evolving understanding of the disease's complex and polygenic pathophysiology. Implementation efforts at academic centers seek to overcome barriers to the broad adoption of pharmacogenomics in the treatment of hypertension. The level of evidence required to support the implementation of pharmacogenomics in clinical practice is considered.
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Inhibitory Effects of Eight Green Tea Catechins on Cytochrome P450 1A2, 2C9, 2D6, and 3A4 Activities.
Satoh, T, Fujisawa, H, Nakamura, A, Takahashi, N, Watanabe, K
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques. 2016;(2):188-97
Abstract
PURPOSE Green tea is a traditional beverage that has been enjoyed by the Japanese to this day. Recently, there has been an increase in the consumption of green tea beverage having high concentrations of catechins, such as (-)-epigallocatechin-3-O-gallate (EGCG). Many people tend to ingest large amounts of catechins through the frequent consumption of green tea beverage, and this dietary habit may lead to unwanted interactions between the catechins in green tea and medicinal drug. METHODS The inhibitory effects of eight green tea catechins on drug metabolizing enzymes, cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4, were investigated in human liver microsomes. Incubation was initiated by the addition of cocktail probe drugs that served as specific substrates for each CYP, and the resulting metabolites were analyzed by LC-MS. RESULTS From a comparison of the fifty percent inhibitory concentration (IC50) values of the eight green tea catechins, it was found that non-gallated catechins did not inhibit CYPs, whereas gallated catechins inhibited all CYPs except CYP2D6. Among them, CYP2C9 was most strongly inhibited by (-)-catechin-3-O-gallate (CG) (7.60 µM), and CYP1A2 was most strongly inhibited by EGCG (8.93 µM). Catechin gallate exhibited non-competitive inhibition of CYP2C9, and its Ki value was 9.76 ± 0.47µM. The present study is the first to report the inhibitory effect of CG on CYP2C9. In contrast, EGCG showed competitive inhibition of CYP1A2, and its Ki value was 14.3 ± 0.09 µM. CONCLUSION Previous reports had predicted that plasma EGCG concentration reached 7.4 µM after ingesting green tea having high concentrations of catechins. That concentration of EGCG is equivalent to one-half to one-third of its Ki value for CYP1A2 and CYP3A4 in this study. The ingestion of beverages containing large amounts of green tea catechins together with drugs that are metabolized by CYP1A2, CYP2C9, and CYP3A4 should be avoided. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
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Electron flow through biological molecules: does hole hopping protect proteins from oxidative damage?
Winkler, JR, Gray, HB
Quarterly reviews of biophysics. 2015;(4):411-20
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Abstract
Biological electron transfers often occur between metal-containing cofactors that are separated by very large molecular distances. Employing photosensitizer-modified iron and copper proteins, we have shown that single-step electron tunneling can occur on nanosecond to microsecond timescales at distances between 15 and 20 Å. We also have shown that charge transport can occur over even longer distances by hole hopping (multistep tunneling) through intervening tyrosines and tryptophans. In this perspective, we advance the hypothesis that such hole hopping through Tyr/Trp chains could protect oxygenase, dioxygenase, and peroxidase enzymes from oxidative damage. In support of this view, by examining the structures of P450 (CYP102A) and 2OG-Fe (TauD) enzymes, we have identified candidate Tyr/Trp chains that could transfer holes from uncoupled high-potential intermediates to reductants in contact with protein surface sites.
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Cytochromes p450 and skin cancer: role of local endocrine pathways.
Slominski, AT, Zmijewski, MA, Semak, I, Zbytek, B, Pisarchik, A, Li, W, Zjawiony, J, Tuckey, RC
Anti-cancer agents in medicinal chemistry. 2014;(1):77-96
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Abstract
Skin is the largest body organ forming a metabolically active barrier between external and internal environments. The metabolic barrier is composed of cytochromes P450 (CYPs) that regulate its homeostasis through activation or inactivation of biologically relevant molecules. In this review we focus our attention on local steroidogenic and secosteroidogenic systems in relation to skin cancer, e.g., prevention, attenuation of tumor progression and therapy. The local steroidogenic system is composed of locally expressed CYPs involved in local production of androgens, estrogens, gluco- and mineralo-corticosteroids from cholesterol (initiated by CYP11A1) or from steroid precursors delivered to the skin, and of their metabolism and/or inactivation. Cutaneous 7-hydroxylases (CYP7A1, CYP7B1 and CYP39) potentially can produce 7-hydroxy/oxy-steroids/sterols with modifying effects on local tumorigenesis. CYP11A1 also transforms 7-dehydrocholesterol (7DHC)→22(OH)7DHC→20,22(OH)2-7DHC→7-dehydropregnenolone, which can be further metabolized to other 5,7- steroidal dienes. These 5,7-dienal intermediates are converted by ultraviolet radiation B (UVB) into secosteroids which show pro-differentiation and anti-cancer properties. Finally, the skin is the site of activation of vitamin D3 through two alternative pathways. The classical one involves sequential hydroxylation at positions 25 and 1 to produce active 1,25(OH)2D3, which is further inactivated through hydroxylation at C24. The novel pathway is initiated by CYP11A1 with predominant production of 20(OH)D3 which is further metabolized to biologically active but non-calcemic D3-hydroxyderivatives. Classical and non-classical (novel) vitamin D analogs show pro-differentiation, anti-proliferative and anticancer properties. In addition, melatonin is metabolized by local CYPs. In conclusion cutaneously expressed CYPs have significant effects on skin physiology and pathology trough regulation of its chemical milieu.