Dataset Information

Effects of cytochrome P450 family 3 subfamily A member 5 gene polymorphisms on daunorubicin metabolism and adverse reactions in patients with acute leukemia.

ABSTRACT: The present study aimed to investigate the association between the genetic polymorphism of cytochrome P450 family 3 subfamily A member 5 (CYP3A5) and the activity of CYP3A and plasma concentrations of daunorubicin (DNR) in patients with acute leukemia. A total of 36 children with newly diagnosed acute lymphoblastic leukemia were enrolled in the study. Polymerase chain reaction (PCR)‑restriction fragment length polymorphism and PCR product sequencing were used to detect the genotype of CYP3A5*3. PCR was then used to express the mRNA expression of CYP3A5. A midazolam probe method was used to detect CYP3A enzyme activity, and DNR concentrations were measured using high performance liquid chromatography. Children with different genotypes had different mRNA expression levels of CYP3A5, and CYP3A enzyme activity in children with the CYP3A5*1 allele was higher, compared with that in children with the CYP3A5*3 allele. In addition, the area under the curve (AUC)0‑24 h and AUC0‑∞ of DNR were significantly different in children with different genotypes, however, no statistically significant differences were found in half‑life or maximum concentration. The AUC of DNR was increased in children with acute lymphatic leukemia who suffered from cardiotoxicity, compared with those in the normal group. The CYP3A5*3 gene polymorphism was closely associated with the mRNA expression of CYP3A5, CYP3A enzyme activity and DNR plasma drug concentration, and exhibited different drug adverse reactions.

SUBMITTER: Huang Z

PROVIDER: S-EPMC5436286 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effects of cytochrome P450 family 3 subfamily A member 5 gene polymorphisms on daunorubicin metabolism and adverse reactions in patients with acute leukemia.

Huang Zhen Z Wang Juxiang J Qian Jiangchao J Li Yuan Y Xu Zhisheng Z Chen Min M Tong Hongfei H

Molecular medicine reports 20170412 6

The present study aimed to investigate the association between the genetic polymorphism of cytochrome P450 family 3 subfamily A member 5 (CYP3A5) and the activity of CYP3A and plasma concentrations of daunorubicin (DNR) in patients with acute leukemia. A total of 36 children with newly diagnosed acute lymphoblastic leukemia were enrolled in the study. Polymerase chain reaction (PCR)‑restriction fragment length polymorphism and PCR product sequencing were used to detect the genotype of CYP3A5*3. ...[more]

PMID: 28440407

Similar Datasets

Project description:BackgroundCytochrome P450 family 17 subfamily A member 1 (CYP17A1) gene encodes a key enzyme in the synthesis and metabolism of steroid hormones and has been associated with various factors, such as hypertension, insulin resistance, and polycystic ovary syndrome. However, whether the gene was associated with type 2 diabetes mellitus (T2DM) has not been reported yet. Therefore, we sought to investigate whether CYP17A1 was associated with T2DM and related traits among Han Chinese.MethodsThree tagging single nucleotide polymorphisms (rs1004467, rs17115149, and rs12413409), in the CYP17A1 gene region were selected and genotyped in a case-control study that included 440 diabetes and 1,320 control subjects. Effects of genetic loci were studied using univariate unconditional logistic regression and multivariate logistic regression analysis adjusted for age, sex, family history, body mass index, smoking, and drinking. Bioinformatics analysis was also conducted using the GEO DataSets and PROMO database to gain hints of possible mechanism.ResultsRs17115149 and rs12413409 polymorphisms were significantly associated with the risk of T2DM, even after adjusting for age, sex, family history, body mass index, smoking, and drinking. In stratified analyses, rs1004467 and rs12413409 showed significant association with T2DM in the older age group (≥65 years) and, in the case of rs12413409, the risk of T2DM was significant in men but not in women. Rs17115149 had significant association with T2DM in the hypertension subgroup, and rs12413409 in the non-hypertension subgroup. Moreover, rs12413409 showed significant association with plasma glucose levels in the recessive model (P = 0.020) among subjects not taking hypoglycemic measures. Bioinformatics analysis revealed significantly higher CYP17A1 gene expression in T2DM patients compared to healthy controls. Finally, the mutant T allele of the rs17115149 polymorphism allowed binding to the RBP-Jkappa transcription factor.ConclusionThis is the first report to identify that variants rs1004467, rs17115149, and rs12413409 of CYP17A1, are related to plasma glucose levels and T2DM among Han Chinese. Our results suggest that CYP17A1 might constitute a risk gene for progression to T2DM.

Project description:In drug development, a system for predicting drug metabolism and drug-induced toxicity is necessary to ensure drug safety. Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) is an important drug-metabolizing enzyme expressed in the liver and small intestine, and predicting CYP3A4-mediated drug metabolism and drug-induced toxicity is essential. We previously developed procedures to differentiate human induced pluripotent stem (iPS) cells into hepatocyte-like cells (HLCs) or intestinal epithelial-like cells (IECs) with a fetal phenotype as well as a highly efficient genome editing technology that could enhance the homologous recombination efficiency at any locus, including CYP3A4. By using human iPS cells and our genome editing technology, we generated CYP3A4-knockout (KO) iPS cell-derived HLCs and IECs for the evaluation of CYP3A4-mediated drug metabolism and drug-induced toxicity. CYP3A4 deficiency did not affect pluripotency and hepatic and intestinal differentiation capacities, and CYP3A4 activity was entirely eradicated by CYP3A4 KO. Off-target effects (e.g., inhibition of bile acid excretion) were hardly observed in CYP3A4-KO cells but were observed in CYP3A4 inhibitor-treated (e.g., ketoconazole) cells. To evaluate whether drug-induced hepatotoxicity and enterotoxicity could be predicted using our model, we exposed CYP3A4-KO HLCs and IECs to acetaminophen, amiodarone, desipramine, leflunomide, tacrine, and tolcapone and confirmed that these cells could predict CYP3A4-mediated toxicity. Finally, we examined whether the therapeutic effects of an anti-hepatitis C virus (HCV) drug metabolized by CYP3A4 would be predicted using our model. CYP3A4-KO HLCs were treated with asunaprevir (antiviral drug metabolized by CYP3A4) after HCV infection, and the anti-viral effect was indeed strengthened by CYP3A4 KO. Conclusion: We succeeded in generating a novel evaluation system for prediction of CYP3A4-mediated drug metabolism and drug-induced toxicity.

Dataset Information

Effects of cytochrome P450 family 3 subfamily A member 5 gene polymorphisms on daunorubicin metabolism and adverse reactions in patients with acute leukemia.

Publications

Effects of cytochrome P450 family 3 subfamily A member 5 gene polymorphisms on daunorubicin metabolism and adverse reactions in patients with acute leukemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets