The Significance of MicroRNAs Expression in Regulation of Extracellular Matrix and Other Drug Resistant Genes in Drug Resistant Ovarian Cancer Cell Lines.

Ovarian cancer rates the highest mortality among all gynecological malignancies. The main reason for high mortality is the development of drug resistance. It can be related to increased expression of drug transporters and increased expression of extracellular matrix (ECM) proteins. Our foremost aim was to exhibit alterations in the miRNA expression levels in cisplatin (CIS), paclitaxel (PAC), doxorubicin (DOX), and topotecan (TOP)-resistant variants of the W1 sensitive ovarian cancer cell line-using miRNA microarray. The second goal was to identify miRNAs responsible for the regulation of drug-resistant genes. According to our observation, alterations in the expression of 40 miRNAs were present. We could observe that, in at least one drug-resistant cell line, the expression of 21 miRNAs was upregulated and that of 19 miRNAs was downregulated. We identified target genes for 22 miRNAs. Target analysis showed that miRNA regulates key genes responsible for drug resistance. Among others, we observed regulation of the ATP-binding cassette subfamily B member 1 gene (ABCB1) in the paclitaxel-resistant cell line by miR-363 and regulation of the collagen type III alpha 1 chain gene (COL3A1) in the topotekan-resistant cell line by miR-29a.

Association of ABCB1 polymorphisms with lipid homeostasis and liver injury response to atorvastatin in the Chinese population.

The present research was to assess the relationship between ABCB1 (G2677T/A, C3435T) polymorphisms and lipid homeostasis as well as risk of liver injury induced by atorvastatin in in-patients from China. The lipid levels (total cholesterol, high-density lipoprotein, triglycerides) as well as metabolic enzymes of hepar (glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase, alkaline phosphatase, γ-glutamyl transpeptidase) in plasma for 162 patients were measured at baseline and after approximately 6 months of atorvastatin treatment. Polymorphisms of the ABCB1 gene were determined using the Snapshot technique. The associations between genetic polymorphisms and lipid levels as well as hepar indexes were evaluated at the end of medical treatment. Based on one-way ANOVA analysis, patients with the 2677GG or 3435TT genotypes showed a remarkable decrease in percentage when the level of TC was above 4.00 mmol·L-1, separately (P < 0.05). There was a significant decrease in percentage in the frequency of patients with the 2677GG genotype (low-density lipoprotein > 2.00 mmol·L-1) (P < 0.05). The level of glutamic-pyruvic transaminase in patients with the 2677GG or 3435CC genotype displayed a significantly increase in percentage, respectively (P < 0.05). The ABCB1 G-C haplotype carriers were associated with an increased risk of AILI. The results provide evidence for clinically individualised utilisation of atorvastatin for lipid homeostasis as well as risk of induced liver injury in the Chinese population.

Variability in expression of the human MDR1 drug efflux transporter and genetic variation of the ABCB1 gene: implications for drug-resistant epilepsy.

Among individuals diagnosed with epilepsy, as many as one in three develop resistance to antiepileptic drugs (AEDs) thus rendering their seizures refractory to treatment. Despite current antiepileptic drugs (AEDs) having a variety of modes of action, seizures in drug-resistant individuals often persist even after treatment with two or more drugs. The underlying cause of this broad resistance is currently under debate, but two dominant theories have emerged and have been widely studied. Here we discuss current literature investigating the "transporter theory", the idea that individuals present with drug resistance due to genetic variability in the ABCB1 gene encoding the efflux transporter multidrug resistance protein 1 (MDR1). Results of in vitro and in vivo studies suggest that variability in the expression of the MDR1 transporter may be closely tied to drug resistance. While there is much support for this hypothesis from molecular and mechanistic studies, population-based studies of ABCB1 polymorphisms are divergent in their conclusions, and there is need for additional investigations.

Genetic variability in ABCB1, occupational pesticide exposure, and Parkinson's disease.

BACKGROUND: Studies suggested that variants in the ABCB1 gene encoding P-glycoprotein, a xenobiotic transporter, may increase susceptibility to pesticide exposures linked to Parkinson's Disease (PD) risk. OBJECTIVES: To investigate the joint impact of two ABCB1 polymorphisms and pesticide exposures on PD risk. METHODS: In a population-based case control study, we genotyped ABCB1 gene variants at rs1045642 (c.3435C/T) and rs2032582 (c.2677G/T/A) and assessed occupational exposures to organochlorine (OC) and organophosphorus (OP) pesticides based on self-reported occupational use and record-based ambient workplace exposures for 282 PD cases and 514 controls of European ancestry. We identified active ingredients in self-reported occupational use pesticides from a California database and estimated ambient workplace exposures between 1974 and 1999 employing a geographic information system together with records for state pesticide and land use. With unconditional logistic regression, we estimated marginal and joint contributions for occupational pesticide exposures and ABCB1 variants in PD. RESULTS: For occupationally exposed carriers of homozygous ABCB1 variant genotypes, we estimated odds ratios of 1.89 [95% confidence interval (CI): (0.87, 4.07)] to 3.71 [95% CI: (1.96, 7.02)], with the highest odds ratios estimated for occupationally exposed carriers of homozygous ABCB1 variant genotypes at both SNPs; but we found no multiplicative scale interactions. CONCLUSIONS: This study lends support to a previous report that commonly used pesticides, specifically OCs and OPs, and variant ABCB1 genotypes at two polymorphic sites jointly increase risk of PD.

Evaluación de l mutación abcb1-1▲ en peros y sus implicaciones terapéutticas y toxicológicas / Analysis of he ccanine abcb1-1▲ mutation and its theraeutic and toxiccological implications

Se analizó la literatura científica de los últimos 10 años en las bases de datos BBCS-LILACS, Fuente Académica, IB-PsycINFO, IB-SSCI, IB-SciELO, SCOPUS y SCIRUS, estudiando las implicaciones terapéuticas de la mutación del gen ABCB1 en perros; esta mutación que consiste en la deleción de 4 pares de bases que provocan un codón de terminación prematuro, es la responsable de la ausencia de la glicoproteína P en la barrera hematoencefálica, la carencia de esta glicoproteína priva al cerebro de la protección de una bomba de eflujo frente a múltiples xenobióticos. Además, se describen los cambios farmacocinéticos y las intoxicaciones medicamentosas resultantes de esta mutación y se presenta una lista, extraída de los distintos estudios, donde se copilan algunos fármacos sustratos para la glicoproteína P y los medicamentos que pueden inhibir dicha glicoproteína, todos ellos capaces de inducir severos efectos adversos en los perros con dicha mutación.

We conducted a review of the results of the studies of the last ten years from the data bases BBCS-LILACS, IB- PsycINFO, IB-SSCI, IB.SciELO, SCOPUS and SCIRUS, about the therapeutic implications of the gene mutation ABCB1 in dogs. This mutation is responsible for the absence of the glycoprotein P in the blood-brain barrier, depriving the brain of an efflux pump to protect against various xenobiotics. Furthermore, we described the pharmacokinetic changes and drug poisoning resulting from this mutation. We also present a list of drug substrates for the glycoprotein P and the medications that can inhibit said glycoprotein, all of them capable of inducing severe side effects in dogs with the mutation.

Associations between the C3435T polymorphism of the ABCB1 gene and drug resistance in epilepsy: a meta-analysis.

OBJECTIVE: A meta-analysis was performed to comprehensively evaluate the correlations between the C3435T polymorphism of ABCB1 (the ATP-binding cassette, subfamily B, member 1 transporter gene) and drug resistance in epilepsy. METHODS: Inclusion and exclusion criteria and a strategy for searching original literature were developed and utilized to search Chinese and non-Chinese databases. Research reports discussing correlations between the ABCB1 C3435T polymorphism and patient responses to anti-epileptic drug (AED) therapy were collected. Comparisons and comprehensive quantitative analyses were conducted using an allele model (C vs. T), and a genotype model (CC vs. CT+TT). In addition, subgroup analyses were performed that divided the included studies according to the race of the study subjects (Asian or Caucasian), based on the geographical region in which each study was conducted. RESULTS: The meta-analysis included a total of 23 publications that examined a total of 3,912 drug-resistant epileptic patients and 4,419 epileptic patients for whom drug treatment was effective. The included studies did not exhibit publication bias. Statistical analyses revealed that the C3435T polymorphism was not significantly correlated with drug resistance in epilepsy. The random-effects model comparing the C and T alleles produced an odds ratio (OR) of 1.10 with a 95% confidence interval (CI) of 0.98-1.25 and P = 0.46. Subgroup analyses suggested that in Caucasian population there are significant differences between resistance group (RN) and control group (N) in both allele model (C vsT: OR = 1.13; 95% CI: 1.03-1.25) and genotype model (CC vsCT+TT: OR = 1.27; 95% CI: 1.08-1.50). CONCLUSION: The ABCB1 C3435T polymorphism is associated with drug resistance in epilepsy in Caucasian population.