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CYP450 enzymes

Poonam Giri, Lakshmikant Gupta, Sneha Naidu, Vipul Joshi, Nirmal Patel, Shyamkumar Giri, Nuggehally R Srinivas
BACKGROUND: The use of poly-pharmacy in the present day clinical therapy has made identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP inhibition potential and/or the metabolic fate for such metabolites. OBJECTIVE: The key objectives were: a) to evaluate the in vitro CYP inhibition potential of select parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of parent drugs and metabolites...
August 16, 2018: Drug Metabolism Letters
Shyam Sundhar Bale, Jeffrey T Borenstein
Animal models such as rats and primates provide body-wide information for drug and metabolite responses, including organ-specific toxicity and any unforeseen side effects on other organs. While effective in the drug screening process, their translatability to humans is limited due to the lack of high concordance and correlation between enzymatic mechanisms, cellular mechanisms and resulting toxicities. A significant mode of failure for safety prediction in drug screening is hepatotoxicity, resulting in ~30% of all safety-related drug failures and withdrawals from the market...
August 16, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Xiaoyu Cheng, Jiahuan Hu, Jinxin Li, Jian Chen, Hui Wang, Tingting Mao, Bin Xue, Bing Li
Silk gland is a major organ of Bombyx mori for the synthesis and secretion of silk protein. Phoxim exposure can be toxic to B. mori and causes a decrease of fibroin synthesis, finally affecting the silk production in industry. To study the mechanism of metabolism and detoxification of silk gland under phoxim exposure, we measured the residual quantity of phoxim in silk gland and hemolymph after phoxim exposure, and the detoxifying enzymes-related genes and enzyme activity were also investigated. Results indicated that the residual amount of phoxim existed up to 24 h in silk gland compared with that in hemolymph, suggesting that phoxim can accumulate in the silk glands within a certain time course...
October 2018: Chemosphere
Gideon Koren, Asher Ornoy
Depression occurs during pregnancy in 3.9-12.8% of the women. The different serotonin reuptake inhibitors (SRIs) are metabolized in the liver by CYP450 enzymes. CYP2D6 metabolizes paroxetine, fluoxetine, duloxetine and venlafaxine, while CYP2C19 deactivates citalopram and escitalopram. Polymorphisms in these enzymes change the metabolic clearance and levels of these drugs. Higher metabolism of most SRIs in late pregnancy results in lower maternal levels, which could result in decreased efficacy. Very few studies have addressed the potential interaction between pregnancy-induced increase in 2D6 metabolism and specific genotypes of the women, suggesting that ultra-rapid and extensive metabolizers exhibit lower serum concentrations than the other slower genotypes...
August 14, 2018: Pharmacogenomics
Min Xu, Huaqiao Tang, XueRong Zhou, Helin Chen, Qi Dong, Yuanli Zhang, Gang Ye, Fei Shi, Cheng Lv, Bo Jing, Changliang He, Ling Zhao, Yinglun Li
Copper nanoparticles (Cu NPs) have widespread application because of their special physicochemical characteristics, however we need to more clearly study the toxicity mechanism of Cu NPs to ensure its safe use in pharmaceutical and animal feed. Thus, the aim of this study was to evaluate the effects and mechanisms of sub-chronic exposure to Cu NPs on renal CYP450 s of rats. In this study, we investigated the effects of Cu NPs on renal oxidative stress, cytokines and histopathology of rats. We found that Cu NPs (200 mg/kg) significantly disordered the function and structure of the kidney and caused a dose-dependent increase in oxidative stress and cytokines, which significantly decreased the levels of mRNA, protein, and activity of CYP450 s...
August 7, 2018: Environmental Toxicology and Pharmacology
Ruijin Li, Lifang Zhao, Li Zhang, Minghui Chen, Jing Shi, Chuan Dong, Zongwei Cai
Ambient fine particulate matter (PM2.5 ) is a complex mixture associated with lung cancer risk. PM2.5 -bound nitro-polycyclic aromatic hydrocarbons (NPAHs) have been demonstrated to possess mutagenicity and carcinogenicity. Previous studies showed that PM2.5 induced DNA damage, whereas there is little knowledge of whether 9-nitroanthracene (9-NA), a typical compound of NPAHs in PM2.5 , causes DNA damage. Also, the regulating mechanisms of PM2.5 and 9-NA in DNA damage and repair are not yet fully established...
September 1, 2017: Toxicology Research
Lauren B Arendse, Jonathan M Blackburn
The effect of non-synonymous single nucleotide polymorphisms (SNPs) on cytochrome P450 (CYP450) drug metabolism is currently poorly understood due to the large number of polymorphisms, the diversity of potential substrates and the complexity of CYP450 function. Previously we carried out in silico studies to explore the effect of SNPs on CYP450 function, using in silico calculations to predict the effect of mutations on protein stability. Here we have determined the effect of eight CYP3A4 and seven CYP2C9 SNPs on the thermostability of proteins in solution to test these predictions...
August 8, 2018: Scientific Reports
Xuebin Shi, Xisha Lin, Yingying Zhu, Yafang Ma, Yingqiu Li, Xinglian Xu, Guanghong Zhou, Chunbao Li
In this work, the effects of different sources of meat protein on liver metabolic enzymes were investigated. Rats were fed for 90 days with semisynthetic diets in which casein was fully replaced by isolated soybean, fish, chicken, pork, or beef proteins. Then, liver proteomics was performed using iTRAQ and LC-ESI-MS/MS. The results indicated that intake of meat protein diets significantly reduced the protein levels of CYP450s, GSTs, UGTs, and SULTs compared to those of the casein and soybean protein diet groups...
August 15, 2018: Journal of Agricultural and Food Chemistry
Huaqiao Tang, Min Xu, Fei Shi, Gang Ye, Cheng Lv, Jie Luo, Ling Zhao, Yinglun Li
Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and mechanisms of action of nano- and micro-copper on the expression and activity of CYP450 enzymes in rat liver. Rats were orally exposed to micro-copper (400 mg/kg), Cu ion (100 mg/kg), or nano-copper (100, 200 and 400 mg/kg) daily for seven consecutive days. Histopathological, inflammatory and oxidative stress were measured in the livers of all rats...
July 23, 2018: International Journal of Molecular Sciences
Uma Saminathan, Pachiyappan Pugalendhi, Suganthi Subramaniyan, Rajendran Jayaganesh
The present study was aimed to investigate the dose dependent chemopreventive activity of brucine against 7, 12-dimethylbenz (a) anthracene induced mammary gland tumorigenesis in rats. The mammary tumor was induced by a single dose of DMBA (25 mg/rat) injected subcutaneously near the mammary gland. We observed reduced body weight and increased in tumor incidence the total number of tumors and tumor volume in DMBA alone injected rats and also observed decreased antioxidant status (SOD, CAT, GPX, and GSH) and increased lipid peroxidation (TBARS and LOOH) in plasma and mammary tissues...
July 20, 2018: Toxicology Mechanisms and Methods
Woo-Young Jeon, Seong Eun Jin, Mee-Young Lee, Chang-Seob Seo, Hyeun-Kyoo Shin, Yong-Bum Kim, Hyekyung Ha
Oryeong-san is a traditional herbal formula that is used for the treatment of common genitourinary diseases in Korea and other Asian countries. However, little is known about its safety and influence on drug metabolism. In the present study, we investigated the subacute toxicity of an Oryeong-san water extract (OSWE) in rats and its effects on activities of drug-metabolizing enzymes. Subacute toxicity was modeled in animals exposed to treatment with the extract at multiple doses. Rats were given OSWE by oral gavage at 0, 1000, 2000 and 5000 mg/kg/day for 4 weeks...
July 17, 2018: Regulatory Toxicology and Pharmacology: RTP
Ying-Zhi Zhang, Yu-Zhu Zuo, Zheng-Hai Du, Jun Xia, Cong Zhang, Hui Wang, Xue-Nan Li, Jin-Long Li
Di (2-ethylhexyl) phthalate (DEHP) is a widely distributed pollutant that is of great concern due to its negative health effects. However, whether DEHP exposure causes liver toxicity in birds remains unclear. To clarify the potential hepatotoxicity of DEHP, quails were exposed to 0, 250, 500 and 1000 mg/kg BW/day DEHP by gavage treatment for 45 days. The livers of DEHP-exposed quails showed histomorphological changes. DEHP exposure induced a significant increase in cytochrome P450 enzyme system (CYP450s) activity (including aniline-4-hydroxylase (AH), aminopyrine N-demethylase (APND), erythromycin N-demethylase (ERND) and NADPH-cytochrome C reductase (NCR)) and in the contents of total cytochrome P450 (CYP450) and cytochrome b5 (Cyt b5) in quail liver...
July 11, 2018: Food and Chemical Toxicology
Hai-Xu Cheng, Ying-Yuan Lu, Xin Wang, Hong Ren, Qiang Li, Shu-Mei Wang, Yu Ding, Ya-Qing Lou, Guo-Liang Zhang
The compound 3,4‑dichlorophenyl‑propenoyl‑sec.‑butylamine (3,4‑DCPB) is an antiepileptic drug. The purpose of the present research was to identify cytochrome P450 (CYP450) responsible for the metabolism of 3,4‑DCPB and evaluate the effects of 3,4‑DCPB on the activities of CYP450 enzymes. 3,4‑DCPB was incubated with rat liver microsomes (RLMs) plus six CYP450 enzyme-specific inhibitors, or six recombinant human CYP450 enzymes (rhCYP450s). The concentrations of 3,4‑DCPB and six CYP450 enzyme-activities probe drugs were detected by high-performance liquid chromatographic (HPLC)...
July 25, 2018: European Journal of Pharmaceutical Sciences
Monpat Chamnanphon, Andrea Gaedigk, Natchaya Vanwong, Nopphadol Nuntamool, Yaowaluck Hongkaew, Apichaya Puangpetch, Chonlaphat Sukasem
The highly polymorphic CYP2D6 gene locus leads to a wide range of enzyme activity. Since there are limited data for Thai, the major aim was to investigate CYP2D6 genetic variation in a large Thai population (n = 920). CYP2D6 genotyping was performed using four different platforms. Genotype call rates of the Luminex xTAG® and AmpliChip CYP450 test were 96.5% and 87.4%, respectively. Based on Luminex xTAG® data, the most common alleles and genotypes were *1 0 (49.6%), *1 (24.6%), *2 (10.8%), *5 (6.7%), *41 (6...
August 1, 2018: Pharmacogenomics
Xiaoming Xu, Zhaojie Cui, Shanshan Wang
Compared to single exposure, chemical mixtures might induce joint toxicity including additive, synergistic and antagonistic effects on both organisms and environment. Owing to the specific toxicity of oxidative stress and binding to proteins, lead (Pb) is generally recognized a non-essential and threatening heavy metal to animals and human. Paraquat (PQ) is a widely used herbicide in agriculture and can trigger oxidative stress as well as Pb. Little information was available about joint effects of the two chemicals on toxicological responses in organisms, especially in fish...
June 28, 2018: Environmental Toxicology and Pharmacology
Sandra Regina Lepri, Daniele Sartori, Simone Cristine Semprebon, Adrivanio Baranoski, Giuliana Castello Coatti, Mario Sergio Mantovani
• Background: Genistein (5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is the most abundant isoflavone in soybean, which has been associated with a lower risk of development of cancer and cardiovascular diseases. Of particular interest regarding cancer preventive properties of flavonoids is their interaction with cytochrome P450 enzymes (CYPs). However, contradictory data report the effect of genistein on expression of СYPs enzymes. • Objective: The aim of this study was to investigate the effects of genistein on cytochrome P450 (CYP) gene expression levels in human hepatocellular carcinoma (HepG2/C3A) and colon adenocarcinoma (HT29) cells...
July 9, 2018: Drug Metabolism Letters
Ling Kong, Jiayi Li, Jilong Wang, Yue Hu, Peijun Meng, Yamin Xiong, Peili Huang
Objective: Quantum dots (QDs) has widely applied in the field of science, whose potential toxic effect has increasingly become a focus concern we need pay attention to in public health. The purpose of this article was to explore the toxicity mechanism with oxidative damage from treatment with QDs at the molecular level through a gene microarray. Methods: Mice were administered aqueously synthesized cadmium telluride QDs (CdTe aqQDs) via intravenous tail injection of a 2 µmol/kg solution (based on the molar mass of Cd), and their kidneys were collected at 1 day in strict accordance with the programs used for treated mice...
2018: Nanotheranostics
Huaqiao Tang, Nana Long, Min Dai, Lin Lin, Jianlong Li, Fenghui Sun, Lijuan Guo
CONTEXT: Citral is used as a potential natural treatment for various infectious diseases. OBJECTIVE: To examine the effect of citral on the mRNA expression and activities of cytochrome P450 (CYP450) enzymes and establish the relationship between citral-induced liver injury and oxidative stress. MATERIALS AND METHODS: ICR mice were randomly divided into citral (20, 200, and 2000 mg/kglow), Tween-80, and control groups (0.9% saline), 10 mice in each group...
December 2018: Pharmaceutical Biology
Shuyan Zhao, Tiankun Liang, Tao Zhou, Dongqi Li, Bohui Wang, Jingjing Zhan, Lifen Liu
Perfluorooctane sulfonamide (FOSA) is an important perfluorooctane sulfonate (PFOS) precursor used for commercial applications. In order to investigate the transformation and responses of selected antioxidant and degradation enzymes of FOSA in the plants, in vivo exposure of soybean (Glycine max L. Merrill) and pumpkin (Cucurbita maxima L.) were conducted in the solution-plant microcosms. FOSA was readily taken up by soybean and pumpkin roots and translocated to shoots, and metabolized to PFOS, perfluorohexane sulfonate (PFHxS) and perfluorobutane sulfonate (PFBS)...
June 20, 2018: Ecotoxicology and Environmental Safety
Hadir M Maher, Nourah Z Alzoman, Shereen M Shehata, Norah O Abanmy
Dasatinib (DAS) is a tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia and in the management of ulcerative colitis (UC). Since some nutraceuticals (e.g. curcumin, olive oil, and cocoa extract) could alter the function of ABC transporters and /or CYP450 enzymes, DAS bioavailability could potentially be affected following their co-administration. This work aims at studying the possibility of PK interaction between DAS and the selected nutraceuticals in UC rats using UPLC- MS/MS...
2018: PloS One
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