scholarly journals Investigation of cytochrome p450 CYP1A2, CYP2D6, CYP2E1 and CYP3A4 gene expressions and polymorphisms in alcohol withdrawal (eng)

2021 ◽  
Vol 24 (3) ◽  
pp. 298-306
Author(s):  
Nazife Taşçıoğlu ◽  
Çetin Saatçi ◽  
Rabia Emekli ◽  
Gulten Tuncel ◽  
Ertuğrul Eşel ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Alcohol Withdrawal ◽  
Gene Expressions ◽  
Cyp3a4 Gene

scholarly journals Potential Role for Human Cytochrome P450 3A4 in Estradiol Homeostasis

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 2911-2919 ◽  
Author(s):  
Ai-Ming Yu ◽  
Katsumi Fukamachi ◽  
Kristopher W. Krausz ◽  
Connie Cheung ◽  
Frank J. Gonzalez
Keyword(s):  
Cytochrome P450 ◽  
Mammary Glands ◽  
Cytochrome P450 3A4 ◽  
Wild Type ◽  
Lactating Mothers ◽  
Human Cytochrome ◽  
Pup Survival ◽  
Cyp3a4 Inhibitors ◽  
Cyp3a4 Gene ◽  
Estradiol Levels

Abstract Previously, a human CYP3A4-transgenic (Tg-CYP3A4) mouse line was reported to exhibit enhanced metabolism of midazolam by cytochrome P450 3A4 (CYP3A4) expressed in small intestine. Here we show that expression of CYP3A4 and murine cyp3a and cyp2b was both age and sex dependent. CYP3A4 was expressed in the livers of male and female Tg-CYP3A4 mice at 2 and 4 wk of age. Since 6 wk, CYP3A4 was undetectable in male livers, whereas it was constitutively expressed in female livers at decreased levels (3- to 5-fold). Pregnenolone 16α-carbonitrile markedly induced hepatic CYP3A4 expression, and the level was higher in females than males. Induction of intrinsic murine cyp3a and cyp2b was also sex dependent. Tg-CYP3A4 females were found to be deficient in lactation, leading to a markedly lower pup survival. The mammary glands of the Tg-CYP3A4 lactating mothers had underdeveloped alveoli with low milk content. Furthermore, β-casein and whey acidic protein mRNAs were expressed at markedly lower levels in Tg-CYP3A4 pregnant and nursing mouse mammary glands compared with wild-type mice. This impaired lactation phenotype was associated with significantly reduced serum estradiol levels in Tg-CYP3A4 mice. A pharmacokinetic study revealed that the clearance of iv administrated [3H]estradiol was markedly enhanced in Tg-CYP3A4 mice compared with wild-type mice. These results suggest that CYP3A4 may play an important role in estradiol homeostasis. This may be of concern for treatment of pregnant and lactating women because CYP3A4 gene expression and enzymatic activity can be potentially modified by CYP3A4 inhibitors or inducers in medications, supplements, beverages, and diet.

scholarly journals CYP3A4*1G gene Polymorphism on Javanese People

2015 ◽  
Vol 16 (2) ◽  
pp. 83
Author(s):  
Em Sutrisna ◽  
Iwan Dwiprahasto ◽  
Erna Kristin
Keyword(s):  
Cytochrome P450 ◽  
Catalytic Activity ◽  
Gene Polymorphism ◽  
Japanese Population ◽  
Genotype Frequency ◽  
Cytochrome P450 3A4 ◽  
Weinberg Equilibrium ◽  
Hardy Weinberg Equilibrium ◽  
Cyp3a4 Gene ◽  
Cytochrome P 450

Most of drugs are metabolized by cytochrome P 450 (CYP) enzyme. Cytochrome P450 3A4 is thecytochrome that is involved in metabolizing more than 60% of all medicine used in human. The variationof this CYP3A4 gene will affect the catalytic activity of this enzyme. Recently, CYP3A4*1G in intron 10 wasfound in Chinese and Japanese population. There is a substitution of G to A at position 82266 in intron 10. Thepurpose of this research was to investigate the frequency of allele and genotype CYP3A4*1G. Samples weretaken from bloods of the subjects of the research. The examination of CYP3A4*1G was conducted by RTLP-PCRmethod.As the results of this research, the frequency of CYP3A4*1G in Javanese people is CYP3A4*1/*1 0.25,CYP3A4*1/*1G 0.55 and CYP3A4*1G/*1G 0.20. Frequency of allele G: 0.53, allele A: 0.47. The Fisher’s exact- testshows that the allele and genotype frequencyis p. 1.000. The allele and genotype frequency of Javanese peopleisstill in Hardy-Weinberg equilibrium.

scholarly journals Possibilities of optimizing approaches to the treatment of resistant epilepsy in children using pharmacogenetic studies data

2019 ◽  
Vol 27 (3) ◽  
pp. 92-96
Author(s):  
Lyudmyla Tantsura ◽  
Olena Pylypets ◽  
Yevhen Tantsura ◽  
Dmytro Tretiakov
Keyword(s):  
Cytochrome P450 ◽  
Gene Polymorphisms ◽  
Statistical Data ◽  
Therapy Monitoring ◽  
Treatment Resistant ◽  
Cytochrome P450 Gene ◽  
P450 Gene ◽  
Cyp2c9 Gene ◽  
Cyp2c19 Gene ◽  
Cyp3a4 Gene

We conducted an observation of 83 children with therapy-resistant forms of epilepsy between the ages of 11 months and 18 years. The presence of CYP2C9, CYP2C19 and CYP3A4 gene polymorphisms was detected in 60 of the examined patients, that is, 72.29 % of them, 33 patients (39.76 %) had CYP2C19 gene polymorphisms, CYP2C9 gene polymorphisms had 17 (20.48 %) children, and 10 (12.05 %) of them had CYP3A4 gene polymorphisms. The frequency of CYP2C19*2 and CYP3A4*1B polymorphisms was signifi cantly higher than in the Ukrainian and other European populations, no statistical data signifi - cance of differences in the frequency of CYP2C9 gene polymorphisms compared with the Ukrainian population was found. CYP2C19 gene polymorphisms are signifi cantly more frequently recorded by us compared to the results obtained by researchers in Russia and Turkey in closely related studies. It is shown that children with cytochrome P450 gene polymorphisms are recommended: more frequent clinical, instrumental, and laboratory monitoring of patients to prevent side eff ects of therapy; monitoring (not a one-time study) of AED concentration in blood plasma. The necessity of conduction of pharmacogenetic research at the stage of debut of epilepsy in the case of suspicion of treatment-resistant form of the disease and in the case of ineffi - ciency or severe side eff ects of the fi rst assigned AED was demonstrated. Key words: children, treatment, resistant epilepsy, cytochrome P450, gene polymorphism.

scholarly journals Differences in expression of genes related to steroidgenesis in abdominal subcutaneous adipose tissue of pregnant women with and without PCOS; a case control study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Neda Emami ◽  
Ashraf Moini ◽  
Parichehreh Yaghmaei ◽  
Vahid Akbarinejad ◽  
Maryam Shahhoseini ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cytochrome P450 ◽  
Pregnant Women ◽  
Polycystic Ovary ◽  
Hydroxysteroid Dehydrogenase ◽  
Mrna Levels ◽  
Gene Expressions ◽  
P450 Monooxygenase ◽  
Expression Levels ◽  
Expression Of Genes

Abstract Background It was reported that steroid-related gene expressions in the adipose tissue (AT) of women differ between women affected with polycystic ovary syndrome (PCOS) and non-PCOS. Although association between PCOS in mother and offspring’s health is a crucial issue, there are few studies focusing on AT of pregnant women suffering from PCOS. Our objectives were to determine the differences between mRNA expression levels of key steroid-converting enzymes in abdominal subcutaneous AT of pregnant women afflicted with PCOS and non-PCOS. Methods Twelve pregnant women with PCOS (case) and thirty six non-PCOS pregnant women (control) (1:3 ratio; age- and BMI-matched) undergoing cesarean section were enrolled for the present study. Expressions of fifteen genes related to steriodogenesis in abdominal subcutaneous AT were investigated using quantitative real-time PCR. Results No significant differences were detected with respect to age, BMI (prior pregnancy and at delivery day), gestational period and parity among pregnant women with PCOS and non-PCOS. Most of the sex steroid-converting genes except 17β-Hydroxysteroid dehydrogenases2 (17BHSD2), were highly expressed on the day of delivery in subcutaneous AT. Women with PCOS showed significantly higher mRNA levels of steroidgenic acute regulator (STAR; P < 0.001), cytochrome P450 monooxygenase (CYP11A1; P < 0.05), 17α-hydroxylase (CYP17A1; P < 0.05), and 11β-Hydroxysteroid dehydrogenase (11BHSD1 and 11BHSD2; P < 0.05). The expression of steroid 21-hydroxylase (CYP21) in non-PCOS was fourfold higher than those of women with PCOS (P < 0.001). There were no significant differences between relative expression of aromatase cytochrome P450 (CYP19A1), 3β-hydroxysteroid dehydrogenase (3BHSD1 and 3BHSD2), and 17BHSD family (1, 3, 5, 7, and 12) between the two groups. Conclusion The expression levels of genes related to sex steroids metabolism were similar to age-matched and BMI- matched pregnant non-PCOS and pregnant women with PCOS at delivery day. However, the alterations in gene expressions involved in glucocorticoids and mineralocorticoids metabolism were shown. It is necessary to point out that further studies regarding functional activity are required. More attention should be given to AT of pregnant women with PCOS that was previously ignored.

scholarly journals Differences in Expression of Genes Related to Steroidgenesis in Abdominal Subcutaneous Adipose Tissue of Pregnant Women with and without PCOS

2020 ◽  
Author(s):  
Neda Emami ◽  
Ashraf Moini ◽  
Parichehreh Yaghmaei ◽  
Vahid Akbarinejad ◽  
Maryam Shahhoseini ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cytochrome P450 ◽  
Pregnant Women ◽  
Polycystic Ovary ◽  
Mrna Levels ◽  
Gene Expressions ◽  
P450 Monooxygenase ◽  
Expression Levels ◽  
Expression Of Genes ◽  
Subcutaneous Adipose

Abstract Background: It was hypothesized that steroid-related gene expressions in the adipose tissue (AT) of women are different between women with and without polycystic ovary syndrome (PCOS). However, little information exists regarding pregnant women suffering from PCOS when interrelationships among maternal PCOS, patient’s quality of life and offspring’s health is a consideration issue in health and diseases. Our objectives were to compare the mRNA expression levels of key steroid-converting enzymes in subcutaneous AT of PCOS vs. non-PCOS pregnant women.Methods: The subjects were 48 pregnant women (12 PCOS and 36 non–PCOS women) undergoing cesarean section, from whom abdominal subcutaneous AT samples were retrieved. Expressions of fifteen genes related to steriodogenesis were investigated using quantitative real-time PCR. Results: No significant differences were found with respect to age, BMI (before pregnancy and at delivery day), gestational period and parity among non-PCOS and PCOS pregnant women. Most of the sex steroid-converting genes except 17β-Hydroxysteroid dehydrogenases2 (17BHSD2), were highly expressed on the day of delivery in subcutaneous AT. PCOS patients showed significantly higher mRNA levels of steroidgenic acute regulator (STAR; P<0.001), cytochrome P450 monooxygenase (CYP11A1; P<0.05), 17α-hydroxylase (CYP17A1; P<0.05), and 11β-Hydroxysteroid dehydrogenase (11BHSD1-2; P<0.05). The expression of steroid 21-hydroxylase (CYP21) in non-PCOS women was 4-fold higher than for PCOS women (P < 0.001). There were no significant differences between relative expression of aromatase cytochrome P450 (CYP19A1), 3β-hydroxysteroid dehydrogenase1-2 (3BHSD1-2), and 17BHSD family (1, 3, 5, 7, and 12) between the two groups.Conclusion: The expression levels of genes related to sex steroids metabolism were similar in age-matched and BMI- matched non-PCOS and PCOS pregnant women at delivery day. However, the alterations in gene expressions involved in glucocorticoids and mineralocorticoid metabolism was shown which warrants further studies regards functional activity. More attention should be given to AT of PCOS mothers that was previously ignored.

scholarly journals Concentrated ambient PM2.5 exposure affects mice sperm quality and testosterone biosynthesis

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8109 ◽  
Author(s):  
Yingying Yang ◽  
Tingting Yang ◽  
Shengxin Liu ◽  
Zhijuan Cao ◽  
Yan Zhao ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Sperm Quality ◽  
Regulatory Protein ◽  
Sperm Concentration ◽  
Hydroxysteroid Dehydrogenase ◽  
Plasma Testosterone ◽  
Gene Expressions ◽  
Exposure System ◽  
Testosterone Concentration ◽  
Testosterone Biosynthesis

Background Studies suggested that PM2.5 exposure could lead to adverse reproductive effects on male animals. However, the underlying mechanism is still not clear. Besides, animals in the majority of previous studies were exposed to PM2.5 through intratracheal instillation which should be improved. In addition, limited amount of research has been conducted in China where the PM2.5 concentration is higher and the PM2.5 components are different. The aim of this work is to explore the effects of concentrated ambient PM2.5 (CAP) on mice sperm quality and testosterone biosynthesis. Methods A total of 12 male C57BL/6 mice were exposed to filtered air (FA) or CAP for 125 days using the Shanghai Meteorological and Environmental Animal Exposure System. The mice sperm concentration, sperm motility, DNA fragmentation index, high DNA stainability and plasma testosterone were analyzed. Testicular histology and sperm morphology were observed through optical microscope. Testosterone biosynthesis related gene expressions were analyzed using real-time PCR, including cytochrome P450 CHOL side-chain cleavage enzyme (P450scc), steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β HSD), 17β-hydroxysteroid dehydrogenase, cytochrome P450 aromatase (P450arom), estrogen receptor (ER), androgen receptor (AR) and follicle stimulating hormone receptor (FSHR). Results Exposure to CAP resulted in disturbance of various stages of spermatogenesis and significant higher percentage of abnormal sperm (FA vs. CAP: 24.37% vs. 44.83%) in mice testis. CAP exposure significantly decreased sperm concentration (43.00 × 106 vs. 25.33 × 106) and motility (PR: 63.58% vs. 55.15%; PR + NP: 84.00% vs. 77.08%) in epididymis. Plasma testosterone concentration were significantly declined (0.28 ng/ml vs. 0.69 ng/ml) under CAP exposure. Notably, the levels of testosterone biosynthesis related genes, StAR, P450scc, P450arom, ER and FSHR were significantly decreased with CAP exposure. Conclusion Concentrated ambient PM2.5 exposure altered mice sperm concentration, motility and morphology, which might be mediated primarily by the decline in testosterone concentration and testosterone biosynthesis process.

scholarly journals Puromycin-based purification of cells with high expression of the cytochrome P450 CYP3A4 gene from a patient with drug-induced liver injury (DILI)

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Shoko Miyata ◽  
Noriaki Saku ◽  
Saeko Akiyama ◽  
Palaksha Kanive Javaregowda ◽  
Kenta Ite ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Liver Injury ◽  
High Expression ◽  
Drug Metabolizing Enzymes ◽  
Drug Induced ◽  
Metabolizing Enzymes ◽  
P450 Gene ◽  
Drug Induced Liver Injury ◽  
Cyp3a4 Gene

Abstract Background Many drugs have the potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4), in hepatocytes. Hepatocytes can be accurately evaluated for drug-mediated CYP3A4 induction; this is the gold standard for in vitro hepatic toxicology testing. However, the variation from lot to lot is an issue that needs to be addressed. Only a limited number of immortalized hepatocyte cell lines have been reported. In this study, immortalized cells expressing CYP3A4 were generated from a patient with drug-induced liver injury (DILI). Methods To generate DILI-derived cells with high expression of CYP3A4, a three-step approach was employed: (1) Differentiation of DILI-induced pluripotent stem cells (DILI-iPSCs); (2) Immortalization of the differentiated cells; (3) Selection of the cells by puromycin. It was hypothesized that cells with high cytochrome P450 gene expression would be able to survive exposure to cytotoxic antibiotics because of their increased drug-metabolizing activity. Puromycin, a cytotoxic antibiotic, was used in this study because of its rapid cytocidal effect at low concentrations. Results The hepatocyte-like cells differentiated from DILI-iPSCs were purified by exposure to puromycin. The puromycin-selected cells (HepaSM or SI cells) constitutively expressed the CYP3A4 gene at extremely high levels and exhibited hepatocytic features over time. However, unlike primary hepatocytes, the established cells did not produce bile or accumulate glycogen. Conclusions iPSC-derived hepatocyte-like cells with intrinsic drug-metabolizing enzymes can be purified from non-hepatocytes and undifferentiated iPSCs using the cytocidal antibiotic puromycin. The puromycin-selected hepatocyte-like cells exhibited characteristics of hepatocytes after immortalization and may serve as another useful source for in vitro hepatotoxicity testing of low molecular weight drugs.

scholarly journals Puromycin selection of cells with a high expression of the cytochrome P450 CYP3A4 gene activity from a patient with drug-induced liver injury (DILI) and their lifespan prolongation using a combination of CDK4R24C, cyclin D1 and TERT

2020 ◽  
Author(s):  
Shoko Miyata ◽  
Noriaki Saku ◽  
Palaksha Kanive Javaregowda ◽  
Kenta Ite ◽  
Masashi Toyoda ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Liver Injury ◽  
High Expression ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Cyp3a4 Gene ◽  
Population Doublings ◽  
Cyp3a4 Induction ◽  
Selection Of

ABSTRACTMany drugs have the potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4), in hepatocytes. Hepatocytes can accurately evaluate drug-mediated CYP3A4 induction as the gold standard for in vitro hepatic toxicology test, but their lot variation is an issue to be solved. Only a limited number of immortalized hepatocyte cells have been reported. In this study, we generated an immortalized cell expressing CYP3A4 from a patient with drug-induced liver injury (DILI). To generate DILI-derived cells with a high expression of CYP3A4, we employed a three-step approach: 1. Differentiation of DILI-induced pluripotent stem cells (DILI-iPSCs); 2. Immortalization of the differentiated cells; 3. Selection of the cells with puromycin. We hypothesize that cells with a high expression of cytochrome P450 genes can survive even after exposure to cytotoxic antibiotics because of high drug-metabolism activity. Puromycin, one of the cytotoxic antibiotics, was used in this study because of its rapid cytocidal effect at a low concentration. Phenotypic studies in vitro revealed that the puromycin-selected cells (HepaSM or SI cells) constitutively expressed the CYP3A4 gene at an extremely high level, and continued to proliferate at least up to 34 population doublings for more than 250 days. The expression profiles were independent of population doublings. Drug-mediated induction test revealed that the cells significantly increased CYP3A4 after exposure to rifampicin, suggesting that the immortalized cells would serve as another useful source for in vitro examination of drug metabolism and CYP3A4 induction.

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