Effect of &lt;b&gt;&lt;i&gt;CYP2C9&lt;/i&gt;&lt;/b&gt; Genetic Polymorphism in a Chinese Population on the Metabolism of Mestranol in vitro

Hu, Jihong; Wang, Li; Li, Wan-shu; Dai, Da‐Peng; Cai, Jian‐Ping; Hu, Guo-Xin

doi:10.1159/000381189

Cited by 8 publications

(6 citation statements)

References 23 publications

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“…With cytochrome P450 (CYP450) enzymes, there are many in vitro drug metabolism − and pharmacokinetics in vivo studies , that investigate the great variation in drug efficacy and toxicity between different individuals. In vitro drug metabolism studies (e.g., human liver microsomes, hepatocytes, etc.)…”

Section: Introductionmentioning

confidence: 99%

From Genotype to Phenotype: Cytochrome P450 2D6-Mediated Drug Clearance in Humans

et al. 2017

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How genotypic variation results in phenotypic differences is still a challenge for biology. In the field of drug metabolism, the means by which specific cytochrome P4502D6 (CYP2D6) genotypes yield different phenotypes at various levels (molecular, cellular, and organismal) is an important question, as differences in CYP2D6 activity can contribute to adverse drug reactions. Herein, the genotype of CYP2D6 was determined along with the absolute content of CYP2D6 and microsomal protein per gram of liver in human liver microsomes, the molecular, cellular (microsomal, tissue, organ), and organismal phenotype of CYP2D6 determined; the effect of genotype on each phenotype of CYP2D6-mediated dextromethorphan clearance (CL) was delineated, and the overall genotype-phenotype relationship for CYP2D6 was charted. We demonstrate that changes in the cellular and organismal CL phenotypes are markedly greater than changes seen at the molecular level. With individuals carrying the 1661CC polymorphism, for example, the most noticeable change took place in organ CL phenotype (4.17-fold), followed by tissue (3.75-fold), organism (3.69-fold), microsomal (3.09-fold), and molecular (1.66-fold) phenotypes. In addition, the biggest intragenotype individual coefficient of variation in organismal phenotype was observed in the 1661GG individuals, which reached 104.5%, followed by that of 100TT, 100CT, 1661GC, 100CC, and 1661CC polymorphisms (102.7%, 62.4%, 53.5%, 49.7%, and 44.8%, respectively). Our study has allowed us to chart the genotype-phenotype relationship for CYP2D6 from the molecular to the organismal level as well as allowed us to determine intragenotype individual variation in phenotype with each genotype.

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Section: Introductionmentioning

confidence: 99%

From Genotype to Phenotype: Cytochrome P450 2D6-Mediated Drug Clearance in Humans

et al. 2017

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“…Cynomolgus CYP2C9 variants p.A82V and p.H344R were associated with lower efavirenz 8-hydroxylation in liver microsomes (Figure ), which is supported by kinetic analysis using recombinant proteins (Table ). Near residue 82, the nonsynonymous variant of human CYP2C9 at residue 78 ( 2C9*31 ) showed reduced catalytic activity compared with the wild type when analyzing recombinant protein using bosentan, carvedilol, diclofenac, fluoxetine, glimepiride, losartan, mestranol, phenytoin, propofol, tolbutamide, and S -warfarin as substrates. − Similarly, in the same studies, near residue 344, the human CYP2C9 variant at residue 343 ( 2C9*54 ) showed lower catalytic activity with bosentan, carvedilol, diclofenac, fluoxetine, losartan, mestranol, and tolbutamide, and higher catalytic activity with phenytoin compared with the wild-type protein. By docking simulation, a low ligand-interaction energy for efavirenz with CYP2C9 p.H344R suggested an unstable interaction between efavirenz and the iron center of the variant protein (Figure A), supporting results of the enzyme assays and kinetic analysis.…”

Section: Discussionmentioning

confidence: 85%

Cytochrome P450 1A1, 2C9, 2C19, and 3A4 Polymorphisms Account for Interindividual Variability of Toxicological Drug Metabolism in Cynomolgus Macaques

Uno

Uehara

Murayama

et al. 2018

Chem. Res. Toxicol.

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Cytochromes P450 (P450s) and their genetic variants in humans are important drug-metabolizing enzymes partly accounting for interindividual variations in drug metabolism and toxicity. However, these genetic variants in P450s have not been fully investigated in cynomolgus macaques, a nonhuman primate species widely used in toxicological studies. In this study, genetic variants found in cynomolgus CYP1A1, CYP2C9 (formerly CYP2C43), CYP2C19 (CYP2C75), and CYP3A4 (CYP3A8) were assessed on functional importance. Resequencing of CYP1A1 in cynomolgus macaques found 18 nonsynonymous variants, of which M121I and V382I were located in SRSs, domains potentially important for P450 function. By further analyzing these two variants, V382I was significantly associated with lower drug-metabolizing activities in the liver for the heterozygotes than the wild types. Similarly, the heterozygotes or homozygotes of CYP2C9 variants (A82V and H344R) and CYP2C19 variant (A490V) showed significantly lower drug-metabolizing activities in the liver than the wild types. Moreover, the homozygotes of CYP3A4 variant (S437N) showed significantly higher activities than the wild type in the liver. Kinetic analyses using recombinant proteins revealed that CYP2C9 variants (A82V and H344R) showed substantially lower K s values than the wild type, although CYP1A1 variant (V382I) showed kinetic parameters similar to the wild type. Likewise, CYP2C19 variant (A490V) showed substantially a lower V max/K m value than the wild type, whereas CYP3A4 variant (S437N) showed a higher V max/K m value than the wild type. These results suggest the toxicologically functional importance of CYP2C9 variants (A82V and H344R), CYP2C19 variant (A490V), and CYP3A4 variant (S437N) for hepatic drug metabolism in cynomolgus macaques.

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“…The anammox reaction uses NH4 + и NO2 -in a stoichiometric ratio of about 1: 1 [19]. In lake ecosystems, this process has been suggested for sediments [82] or for the chemocline of several meromictic lakes: Lake Tanganyika [83], Lake Rassnitz (Germany; [84]) and Lake Lugano (Switzerland, Italy; [85]). However, for Lake Svetloe, the anammox process is the least likely, since the bacteria Planctomycetes that carry out this process [81,86] have not been found in the lake monimolimnion [35].…”

Section: Figurementioning

confidence: 99%

Distribution of Dissolved Nitrogen Compounds in the Water Column of a Meromictic Subarctic Lake

Vorobyeva¹,

Chupakova²,

Chupakov³

et al. 2021

Preprint

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In order to better understand the biogeochemical cycle of nitrogen in meromictic lakes, which can serve as a model for past aquatic environments, we measured dissolved concentrations of nitrate, nitrite, ammonium and organic nitrogen in deep (39 m maximal depth) subarctic Lake Svetloe (NW Russia). The lake is a rare type of freshwater meromictic water boy with high concentrations of methane, ferrous iron, manganese and low concentrations of sulfates and sulfides in the monimolimnion. In the oligotrophic mixolimnion, the concentration of mineral forms of nitrogen decreased in summer compared to winter, likely due to phytoplankton bloom. The decomposition of the bulk of organic matter occurs under microaerophilic/anaerobic conditions of the chemocline and accompanied by the accumulation of nitrogen in the form of N-NH4 in the monimonimlion. We revealed a strong relationship between methane and nitrogen cycles in the chemocline and monimolimnion horizons. The nitrate concentrations in Lake Svetloe varied in the range from 9 to 13 μM throughout the water column. This fact is rare for meromictic lakes, where nitrate concentrations up to 13 µM are found in the monimolimnion zone down to the bottom layers. We hypothesize, in accord with available data for other stratified lakes, that under conditions of high concentrations of manganese and ammonium at the boundary of redox conditions and below, anaerobic nitrification with the formation of nitrates occurs. Overall, most of organic matter in Lake Svetloe undergoes biodegradation essentially under microaerophilic/anaerobic conditions of the chemocline and the monimolimnion. Consequently, the manifestation of the biogeochemical nitrogen cycle is expressed in these horizons in the most vivid and complex relationship with other cycles of elements.

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Effect of <b><i>CYP2C9</i></b> Genetic Polymorphism in a Chinese Population on the Metabolism of Mestranol in vitro

Cited by 8 publications

References 23 publications

From Genotype to Phenotype: Cytochrome P450 2D6-Mediated Drug Clearance in Humans

From Genotype to Phenotype: Cytochrome P450 2D6-Mediated Drug Clearance in Humans

Cytochrome P450 1A1, 2C9, 2C19, and 3A4 Polymorphisms Account for Interindividual Variability of Toxicological Drug Metabolism in Cynomolgus Macaques

Distribution of Dissolved Nitrogen Compounds in the Water Column of a Meromictic Subarctic Lake

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