Genetic variation and haplotype structures of the glutathione S-transferase genes GSTA1 and GSTA2 in Japanese colorectal cancer patients.
ABSTRACT Glutathione S-transferases (GSTs) play a vital role in the phase II biotransformation of many chemicals, including anticancer drugs. In this study, to elucidate the haplotype structures of the two closely related alpha-class genes GSTA1 and GSTA2, we screened for genetic variation in 214 Japanese colorectal cancer patients who received oxaliplatin-based chemotherapy. By direct resequencing of the 5'-flanking region, all the exons, and their flanking introns for 107 patients, 29 and 27 variants were identified in GSTA1 and GSTA2, respectively. The known functional single nucleotide polymorphisms (SNPs) -567T>G, -69C>T, and -52G>A in GSTA1*B were found at allele frequencies of 0.140. Of the four major GSTA2 allelic variants reported previously (GSTA2*A, *B, *C, and *E), only GSTA2*B (frequency = 0.154), *C (0.706), and *E (0.140) were detected. Following linkage disequilibrium analysis, haplotypes of both genes were separately estimated. Then, rapid genotyping methods for 7 and 6 SNPs tagging common haplotypes of GSTA1 and GSTA2, respectively, were developed using the single-base extension assay, and an additional 107 patients were genotyped. Finally, haplotype combinations of both genes were classified into 3 major types: GSTA1*A-GSTA2*C, GSTA1*A-GSTA2*B, and GSTA1*B-GSTA2*E. These findings will be useful in pharmacogenomic studies on xenobiotics including anticancer drugs.
SourceAvailable from: Marzena Skrzypczak-Zielinska[Show abstract] [Hide abstract]
ABSTRACT: General anesthesia may lead in patients to unexpected and adverse reactions including toxicity. Glutathione S-transferases (GSTs) are enzymes responsible for the detoxification process of anesthetic agents. Plasma and urine GST measurements are used in multiple studies as a hepatocellular integrity or renal injury indicator. The importance of GST enzyme measurements in monitoring the hepatotoxic and nephrotoxic effect in anesthetized patients is presented. The biochemical function and specific properties of GST render it a prognostic biomarker. This review demonstrates that GST can be valuable and promising toxicity indicator in patients undergoing general anesthesia.Journal of Clinical Anesthesia 11/2014; 27(1). DOI:10.1016/j.jclinane.2014.07.002 · 1.21 Impact Factor
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ABSTRACT: Glutathione S-transferases (GSTs) family of enzymes is best known for their cytoprotective role and their involvement in the development of anticancer drug resistance. Recently, emergence of non-detoxifying properties of GSTs has provided them with significant biological importance. Addressing the complex interactions of GSTs with regulatory kinases will help in understanding its precise role in tumor pathophysiology and in designing GST-centered anticancer strategies.Cancer Chemotherapy and Pharmacology 08/2014; DOI:10.1007/s00280-014-2566-x · 2.57 Impact Factor
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ABSTRACT: Allogenic hematopoietic stem cell transplantation (HSCT) is a well established but complex treatment option for malignant and non-malignant disorders in pediatric patients. Most commonly used myeloablative and non-myeloablative conditioning regimens in children comprise alkylating agents, such as busulfan (BU) and cyclophosphamide. Inter-individual variability in the pharmacokinetics of BU can result in altered conditioning of the patient and therefore lead to relapse or rejection due to under exposures, or occurrence of toxicities due to over exposures. With the introduction of the intravenous formulation of BU, this variability has been reduced but still cannot be fully predicted. Inter and intra-individual variability of BU kinetics is more common in children compared to adults and toxicity of BU based regimens is still a concern. It has been hypothesized that some of this variability in BU pharmacokinetics and treatment outcomes, especially the toxicity, might be predicted by genetic variants of enzymes involved in the metabolism of BU. This review intends to summarize the studies performed to date on the pharmacokinetics and pharmacogenetics of BU based conditioning, specifically in relation to children.Current Drug Metabolism 01/2014; vol. 15(No 3):pp. 251-264. · 3.49 Impact Factor