scholarly journals CYP2B6 Gene

2020 ◽  
Author(s):  
Keyword(s):  
Cyp2b6 Gene

Polymorphism of p-450 cytochrome detoxication genes in adolescents depending on the degree of contamination of the organism by heavy metals

2020 ◽  
Vol 99 (5) ◽  
pp. 478-482
Author(s):  
N. P. Setko ◽  
A. G. Setko ◽  
Ekaterina V. Bulycheva ◽  
A. V. Tyurin ◽  
E. Yu. Kalinina
Keyword(s):  
Heavy Metals ◽  
Environmental Factors ◽  
Heavy Metal Contamination ◽  
Atomic Absorption Spectrophotometry ◽  
The Body ◽  
Lead And Cadmium ◽  
Cyp2b6 Gene ◽  
Cytochrome P 450 ◽  
Gene Cyp1a1 ◽  
Group 1

Introduction. Changes in the body of children and adolescents aimed at adapting to environmental factors are determined by genetic polymorphism in xenobiotic biotransformation genes, determining the degree of susceptibility of the child’s body to pollutants, which is the basis of modern personalized preventive medicine when managing risks to the health of the child population under the influence of environmental factors. Material and methods. Trace elements, including heavy metals, lead and cadmium, were determined in the hair of 256 practically healthy teenagers by atomic absorption spectrophotometry. Depending on the level of content of the latter, two groups of adolescents were formed to determine six genes of the cytochrome P-450 family. Group 1 consisted of adolescents whose cadmium lead content exceeded the average Russian indices. The second group included adolescents whose heavy metals were above the level of average Russian standards. Results. Studies have shown that in adolescents of the 1st group, compared with the data of adolescents of the 2nd group, an increase in the number of carriers of two mutant alleles at the locus rs 1048943 (gene CYP1A1) is 3.08 times, rs 464621 (gene CYP1A1) is 1. 8 times; locus rs 2069522 (CYP1A2 gene) 3.63 times; locus rs 1799853 (CYP2C9 * 2 gene) 4.5 times; locus rs 1057910 (gene CYP2C9 * 3) 3.8 times and locus rs 2279343 (gene CYP2B6) 4.25 times. Moreover, carriers of two normal alleles in adolescents of the first group at the locus rs 1048943 (gene CYP1A1) were 5.14 times; locus rs 2279343 (CYP2B6 gene) was 6.5 fold less than among adolescents of the 2nd group; and at the locus rs 464621 (gene CYP1A1), rs 2069522 (gene CYP1A2), rs 1799853 (gene CYP2C9 * 2), rs 1057910 (gene CYP2C9 * 3) there were no carriers of normal homozygotes. Conclusion. Group 1 adolescents with heavy metal contamination of the body are carriers significantly in a greater number of pathological mutations in the genes of the cytochrome P-450 detoxification system in comparison with data from group 2 adolescents.

scholarly journals The constitutive androstane receptor is a novel therapeutic target facilitating cyclophosphamide-based treatment of hematopoietic malignancies

Blood ◽  
2013 ◽  
Vol 121 (2) ◽  
pp. 329-338 ◽  
Author(s):  
Duan Wang ◽  
Linhao Li ◽  
Hui Yang ◽  
Stephen S. Ferguson ◽  
Maria R. Baer ◽  
...  
Keyword(s):  
Constitutive Androstane Receptor ◽  
Leukemia Cell ◽  
Systemic Exposure ◽  
Hepatic Metabolism ◽  
Leukemia Cells ◽  
Endogenous Expression ◽  
Cellular Environment ◽  
Cyp2b6 Gene ◽  
Pharmacologically Active

Abstract Cyclophosphamide (CPA) is one of the most widely used chemotherapeutic prodrugs that undergoes hepatic bioactivation mediated predominantly by cytochrome P450 (CYP) 2B6. Given that the CYP2B6 gene is primarily regulated by the constitutive androstane receptor (CAR, NR1I3), we hypothesize that selective activation of CAR can enhance systemic exposure of the pharmacologically active 4-hydroxycyclophosamide (4-OH-CPA), with improved efficacy of CPA-based chemotherapy. In this study, we have developed a unique human primary hepatocyte (HPH)–leukemia cell coculture model; the chemotherapeutic effects of CPA on leukemia cells can be directly investigated in vitro in a cellular environment where hepatic metabolism was well maintained. Our results demonstrated that activation of CAR preferentially induces the expression of CYP2B6 over CYP3A4 in HPHs, although endogenous expression of these enzymes in leukemia cells remains negligible. Importantly, coadministration of CPA with a human CAR activator led to significantly enhanced cytotoxicity in leukemia cells by inducing the apoptosis pathways, without concomitant increase in the off-target hepatotoxicity. Associated with the enhanced antitumor activity, a time and concentration-dependent increase in 4-OH-CPA formation was observed in the coculture system. Together, our findings offer proof of concept that CAR as a novel molecular target can facilitate CPA-based chemotherapy by selectively promoting its bioactivation.

scholarly journals Variations in Infant CYP2B6 Genotype Associated with the Need for Pharmacological Treatment for Neonatal Abstinence Syndrome in Infants of Methadone-Maintained Opioid-Dependent Mothers

2017 ◽  
Vol 34 (09) ◽  
pp. 918-921 ◽  
Author(s):  
Poppy McLaughlin ◽  
Cheryl Gillis ◽  
Michael Osselton ◽  
Helen Mactier
Keyword(s):  
Pharmacological Treatment ◽  
Maternal Blood ◽  
Maternal Plasma ◽  
Genomic Variation ◽  
Neonatal Abstinence Syndrome ◽  
Abstinence Syndrome ◽  
Buccal Swabs ◽  
Cyp2b6 Gene ◽  
Observational Cohort

Background Neonatal abstinence syndrome (NAS) in infants of methadone-maintained opioid-dependent (MMOD) mothers cannot be predicted in individual cases. We investigated whether variation in infant genotype is associated with severity of NAS. Methods This is a pilot observational cohort study of 21 MMOD mothers and their newborns. Infant buccal swabs were obtained soon after delivery, together with a maternal blood sample for the determination of maternal plasma methadone concentration. Genomic variation in five opioid-related genes (ABCB1, COMT, CYP2B6, CYP2D6, and OPRM1) was ascertained from infant buccal swabs and related to need for pharmacological treatment of NAS. Results Out of 21 infants, 11 (52%) required treatment for NAS. Mothers of treated infants tended to have been prescribed higher doses of methadone, but plasma methadone concentrations did not differ between mothers of treated or untreated babies. Treated and untreated babies did not differ in terms of method of feeding. Treated infants were more likely to carry the normal (homozygous) allele at 516 and 785 regions of CYP2B6 gene (p = 0.015 and 0.023, respectively). There were no differences in any other genes between infants who did or did not require treatment for NAS. Conclusion Genomic variation in CYP2B6 may explain, at least in part, severity of NAS.

Impact of polymorphisms in the CYP2B6 gene on the pharmacokinetics of cyclophosphamide and thiotepa

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13062-13062
Author(s):  
C. Ekhart ◽  
A. Huitema ◽  
S. Rodenhuis ◽  
J. H. Beijnen
Keyword(s):  
A Priori ◽  
Plasma Concentrations ◽  
Hepatic Clearance ◽  
High Dose Chemotherapy ◽  
Pharmacokinetic Parameters ◽  
High Dose ◽  
Severe Toxicity ◽  
Active Metabolites ◽  
Increased Risk ◽  
Cyp2b6 Gene

13062 Background: Cyclophosphamide and thiotepa are frequently used simultaneously as part of high dose chemotherapy regimens for solid tumours. Although generally well tolerated, severe toxicity may occur. Relationships between pharmacokinetics and toxicity have been identified. Cyclophosphamide and thiotepa are both metabolised by cytochrome P450 (CYP)enzymes, resulting in the active metabolites 4-hydroxycyclophosphamide and tepa respectively. CYP2B6 and CYP3A4 are the major metabolising isozymes for both compounds. In this study we investigated the relationship between polymorphisms of the CYP2B6 gene and the hepatic clearance of cyclophosphamide and thiotepa in order to identify a priori patients at risk for severe toxicity. Methods: CYP2B6*2 (C64T) and variants A785G, C1459T and G516T were identified by PCR and sequencing samples from 82 patients receiving a high dose regimen consisting of cyclophosphamide (4–6 g/m2), thiotepa (320–480 mg/m2) and carboplatin (AUC 13–20 mg*min/ml). Plasma concentrations of thiotepa, cyclophosphamide and metabolites were determined using a validated LC-MS/MS method. Individual pharmacokinetic parameters were obtained using nonlinear mixed effects modelling. Results: A total of 82 patients was included. Not all data of the various variants were available. All investigated variants had an allele frequency of > 3% in the population. While 94% of the patients had the wildtype genotype for CYP2B6*2, 6% were heterozygous. Heterozygous patients for *2 had a lower hepatic clearance of thiotepa compared to wildtype patients (11.7 l*h−1 vs 14.4 l*h−1) (P=0.03). All other allelic variants investigated showed no effect on either hepatic clearance of thiotepa or cyclophosphamide. Conclusions: This study demonstrates that the hepatic clearance of thiotepa is reduced in patients with a heterozygous CYP2B6*2 genotype. Patients with this genotype may have an increased exposure to thiotepa and may, therefore, be at increased risk for organ toxicity. No significant financial relationships to disclose.

Multiple Novel Nonsynonymous CYP2B6 Gene Polymorphisms in Caucasians: Demonstration of Phenotypic Null Alleles

2004 ◽  
Vol 311 (1) ◽  
pp. 34-43 ◽  
Author(s):  
Thomas Lang ◽  
Kathrin Klein ◽  
Tanja Richter ◽  
Arne Zibat ◽  
Reinhold Kerb ◽  
...  
Keyword(s):  
Gene Polymorphisms ◽  
Null Alleles ◽  
Cyp2b6 Gene

scholarly journals Inter-ethnic genetic variations and novel variant identification in the partial sequences of CYP2B6 gene in Pakistani population

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11149
Author(s):  
Sagheer Ahmed ◽  
Hizbullah Khan ◽  
Asifullah Khan ◽  
Muhammad Hanif Bangash ◽  
Abrar Hussain ◽  
...  
Keyword(s):  
Ethnic Groups ◽  
Genetic Variance ◽  
Strong Association ◽  
Hypervariable Region ◽  
Nucleotide Polymorphisms ◽  
Pakistani Population ◽  
Splicing Pattern ◽  
Novel Variant ◽  
Cyp2b6 Gene ◽  
Novel Snp

Background Some single nucleotide polymorphisms (SNPs) in the cytochrome P450 (CYP)2B6 gene lead to decreased enzyme activity and have an impact on drug metabolism. The present study was designed to investigate the patterns of genetic distinction across a hypervariable region of the CYP2B6 gene, known to contain important SNPs, i.e. rs4803419 and rs3745274, among five major ethnic groups of the Pakistani population. Methods Arlequin v3.5.DnaSPv6.12. and network 5 resources were used to analyze population genetic variance in the partial CYP2B6 gene sequences obtained from 104 human samples belonging to Punjabi, Pathan, Sindhi, Seraiki and Baloch ethnicities of Pakistan. The partial CYP2B6 gene region analyzed in the current study is previously known to possess important SNPs. Results The data analyses revealed that genetic variance among samples mainly came from differentiation within the ethnic groups. However, significant genetic variation was also found among the various ethnic groups. The high pairwise Fst genetic distinction was observed between Seraiki and Sindhi ethnic groups (Fst = 0.13392, P-value = 0.026) as well as between Seraiki and Balochi groups (Fst = 0.04303, P-value = −0.0030). However, the degree of genetic distinction was low between Pathan and Punjabi ethnic groups. Some SNPs, including rs3745274 and rs4803419, which are previously shown in strong association with increased plasma Efavirenz level, were found in high frequency. Besides, a novel SNP, which was not found in dbSNP and Ensemble databases, was identified in the Balochi ethnicity. This novel SNP is predicted to affect the CYP2B6 splicing pattern. Conclusion These results may have significant implications in Pakistani ethnicities in the context of drugs metabolized by CYP2B6, especially in Seraiki and Balochi ethnicity. The novel heterogeneous SNP, found in the present study, might lead to altered drug-metabolizing potential of CYP2B6 and, therefore, may be implicated in non-responder phenomenon.

scholarly journals Interindividual Variability of Cytochromes P450 2B Mediated Oxidation in Human Liver

2021 ◽  
Author(s):  
Abdulmohsen Alrohaimi ◽  
Bader Alrohaimi ◽  
Nada Alruwais ◽  
Kholoud Aldmasi
Keyword(s):  
Interindividual Variability ◽  
Stop Codon ◽  
Cytochromes P450 ◽  
Premature Stop Codon ◽  
Pregnane X Receptor ◽  
Alcohol Ingestion ◽  
Drug Biotransformation ◽  
Cyp2b6 Gene ◽  
Genetic And Environmental Factors ◽  
Mediated Oxidation

The cytochromes P450 (CYPs) are a group of enzymes that are primarily responsible for oxidative drug biotransformation in people. CYP2B6, which metabolizes numerous drugs including bupropion, propofol and other drug shows great variability in rates of drug oxidation between individuals. In this chapter we discuss the contribution of selected genetic and environmental factors to this variability. Several studies identified and quantified the most common CYP2B6 mRNA splice such as deletion of exons 4 to 6 and of exon 4 which were significantly and negatively correlated with CYP2B6 protein and enzyme activity. CYP2B6 gene expression is highly inducible by phenobarbital. Alcohol ingestion has been associated with increased CYP2B6 levels this involves the constitutive androstane receptor (CAR) and/or the pregnane X receptor (PXR). CYP2B7 is considered a pseudogene because of the presence of a single premature stop codon (TGA) in exon 7. In 10 out of 24 African-Americans (but none out of 48 European-Americans) there is a single nucleotide polymorphism that results in an arginine codon instead of a stop codon (X378R). The results of these studies identify certain CYP2B6 genetic polymorphisms, mRNA splicing variants, and alcohol ingestion as significant factors that determine interindividual variability of CYP2B-mediated oxidation of drugs in people.

scholarly journals Prevalence of MDR1 C3435T and CYP2B6 G516T Polymorphisms among HIV-1 Infected South African Patients

2012 ◽  
Vol 32 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Tracy Madimabi Masebe ◽  
Pascal Obong Bessong ◽  
Julius Nwobegahay ◽  
Roland Ndip Ndip ◽  
Debra Meyer
Keyword(s):  
South African ◽  
Rflp Analysis ◽  
Polymerase Chain Reaction Analysis ◽  
Population Based ◽  
Significant Difference ◽  
Cyp2b6 Gene ◽  
Polymerase Chain ◽  
African Patients ◽  
Hiv Drugs ◽  
Selection Of

Data on genetic polymorphisms associated with response to anti-HIV drugs has accumulated over the years. Information on how polymorphisms influence drug metabolism and transport to target sites is important in guiding dosage or selection of appropriate alternative therapies. This study determined the frequency of MDR1 C3435T and CYP2B6 G516T polymorphisms associated with the transport and metabolism of efavirenz and nevirapine, in a population of South African HIV infected patients. In addition, association of polymorphisms with immunologic and virologic factors was investigated. A 207bp of MDR1 exon 26 and a 161bp of CYP2B6 exon 4 were obtained from patients by polymerase chain reaction. Analysis of population-based sequences of MDR1 revealed a frequency of 89% and 11% of C and T alleles respectively (n=197; X2= 0.974;p=0.324). Restriction fragment length polymorphism (RFLP) analysis of the CYP2B6 gene revealed a prevalence of 9.5% of GG, 78.4% of GT and 12.1% of TT genotype (n= 199; X2= 65.204; p=0.00). There was no significant difference between immune recovery and decline in viral load (n=53), with genotype after repeated calculations of analysis of variance (ANOVA).

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