Plasma Levels of 25-Hydroxyvitamin D3andIn VivoMarkers of Cytochrome P450 3A Activity in Swedes and Koreans: Effects of a Genetic Polymorphism and Oral Contraceptives

2014 ◽  
Vol 115 (4) ◽  
pp. 366-371 ◽  
Author(s):  
Hanna Nylén ◽  
Linda Björkhem-Bergman ◽  
Lena Ekström ◽  
Hyung-Keun Roh ◽  
Leif Bertilsson ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Genetic Polymorphism ◽  
Oral Contraceptives ◽  
Plasma Levels ◽  
Cytochrome P450 3A

scholarly journals Breast cancer: Role of pharmacogenetics in tamoxifen therapy

2016 ◽  
Vol 1 (1) ◽  
pp. 10
Author(s):  
Smriti Mishra ◽  
Manish Manish
Keyword(s):  
Breast Cancer ◽  
Cytochrome P450 ◽  
Genetic Polymorphism ◽  
Clinical Outcome ◽  
Tamoxifen Therapy ◽  
Uridine Diphosphate ◽  
Cytochrome P450 2D6 ◽  
Cytochrome P450 3A ◽  
P450 2D6

<p><span>The role of pharmacogenetics in the personalization of tamoxifen therapy has relevance in the management of breast cancer. Since Tamoxifen is a pro-drug, genetic polymorphism in Phase I and Phase II drug metabolizing enzymes involved in the bioconversion of tamoxifen to therapeutically active metabolites is critical in determining therapeutic efficacy and adverse drug reactions of the therapy in breast cancer patients. In this review, the role of pharmacogenetics in the personalization of tamoxifen therapy has been discussed. Since, metabolism of tamoxifen by Cytochrome P450 2D6 is significant in determining the therapeutic efficacy of the drug, most of the clinical evidence on tamoxifen pharmacogenetics have been correlated with cytochrome p450 2D6 genetic polymorphism. However, there is discordance in the clinical data, and one of the reasons is the incomplete analysis of all the alleles of cytochrome p450 2D6. International Tamoxifen Pharmacogenomics Consortium has been formed to assess   the discordance. There are also clinical evidences associating genetic polymorphism in cytochrome P450 3A, 2C9, 2C19, Uridine diphosphate –glucuronosyltransferases and Sulfotransferases with clinical outcome of tamoxifen therapy. However, associations of genetic polymorphism in cytochrome P450 3A, 2C9, 2C19, Uridine diphosphate –glucuronosyltransferases and Sulfotransferases with clinical outcome in populations of different ethnicity are unexplored. Evidences on  the association of genetic polymorphisms and the clinical outcome have been summarized in the Table.  Since cost, statistically significant sample population size, labor and ethical issues are the major concerns of a pharmacogenetic investigation; the significance of bottom-up approach in pharmacogenetics has been discussed.</span></p>

Associations of CYP2A6 Gene Polymorphism with Smoking Status Among Jordanians: Gender-Related Differences

2019 ◽  
Vol 20 (9) ◽  
pp. 765-770 ◽  
Author(s):  
Hana M. Hammad ◽  
Amer Imraish ◽  
Belal Azab ◽  
Al M. Best ◽  
Yousef S. Khader ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Genetic Polymorphism ◽  
Smoking Status ◽  
Hepatic Enzyme ◽  
Nicotine Metabolism ◽  
Significant Frequency ◽  
Cytochrome P450 2A6 ◽  
Study Population ◽  
Major Metabolic Pathway ◽  
Cyp2a6 Gene

Background: Cytochrome P450 2A6 enzyme (CYP2A6), an essential hepatic enzyme involved in the metabolism of drugs, is responsible for a major metabolic pathway of nicotine. Variation in the activity of polymorphic CYP2A6 alleles has been implicated in inter-individual differences in nicotine metabolism. Aims: The objective of the current study was to assess the association between the smoking status and the cytochrome P450 2A6 enzyme (CYP2A6) genotype in Jordanians. Methods: In the current study, 218 (117 Male and 101 female) healthy unrelated Jordanian volunteers were recruited. CYP2A6*1B, CYP2A6*4 and CYP2A6*9 were determined and correlated with subject smoking status. Results: *1A/*1A was the most common genetic polymorphism in the overall study population, with no significant frequency differences between smokers and non-smokers. When the population was divided according to gender, only male smokers showed a significant correlation between genotype and smoking status. Considering the CYP2A6*9 genotype, the results showed differences in distribution between smokers and non-smokers, but only women showed a significant association between CYP2A6*9 allele genotype and smoking status. Conclusion: The results of this study show that there is a significant association between CYP2A6*9 genotype and smoking status. They also show that CYP2A6 genotype is significantly influenced by gender.

scholarly journals Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification

2021 ◽  
Author(s):  
Lawrence Howell ◽  
Rosalind E. Jenkins ◽  
Stephen Lynch ◽  
Carrie Duckworth ◽  
B. Kevin Park ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Rna Polymerase Ii ◽  
Liver Tissue ◽  
Drug Disposition ◽  
Multiple Drug ◽  
Proteomic Profiling ◽  
Cytochrome P450 3A ◽  
Drug Induced

AbstractHepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10–1000 µM) and irinotecan (1–100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.

Debate resolved: there are differential effects of serotonin selective reuptake inhibitors on cytochrome P450 enzymes

1998 ◽  
Vol 12 (4_suppl) ◽  
pp. S89-S97 ◽  
Author(s):  
Sheldon H. Preskorn
Keyword(s):  
Cytochrome P450 ◽  
Plasma Levels ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Serotonin Reuptake Inhibitors ◽  
Original Position ◽  
Selective Serotonin ◽  
Cytochrome P450 Enzymes ◽  
Extensive Body ◽  
Cyp 2D6

In 1993, it was first proposed that an important difference between selective serotonin reuptake inhibitors (SSRIs) was the degree of inhibition of the cytochrome P450 (CYP) enzyme 2D6 that they produced under usually dosing conditions (Preskorn, 1993). Specifically, fluoxetine and paroxetine, in contrast to sertraline, were identified as causing substantial increases in the plasma levels of coadministered drugs, which were principally dependent on CYP 2D6 for their metabolism. Over the next 5 years, this position was hotly contested (Preskorn and Nemeroff, 1997). However, an extensive body of research has now accumulated, which incontrovertibly supports the original position. This paper will reviews this research and extends the discussion to all five SSRIs and four other important CYP enzymes: 1A2, 2C9/10, 2C19, and 3A3/4.

Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4β-hydroxycholesterol

2011 ◽  
Vol 67 (7) ◽  
pp. 715-722 ◽  
Author(s):  
Hanna Nylén ◽  
Sofia Sergel ◽  
Lisa Forsberg ◽  
Synnöve Lindemalm ◽  
Leif Bertilsson ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 3A
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