GSTM1 and GSTT1 double null genotypes determining cell fate and proliferation as potential risk factors of relapse in children with hematological malignancies after hematopoietic stem cell transplantation.

PURPOSE This study aimed to retrospectively evaluate the genetic association of null variants of glutathione S-transferases GSTM1 and GSTT1 with relapse incidence in children with hematological malignancies (HMs) undergoing busulfan (BU)- containing allogeneic hematopoietic stem cell transplantation (HSCT) and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized lymphoblastoid cell lines (LCLs) and tumor THP1 GST gene-edited cell models. METHODS GSTM1- and GSTT1-null alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of GSTM1- and GSTT1-null variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell death studies were conducted in GSTs- null and non-null LCLs and CRISPR-Cas9 gene-edited THP1 leukemia cell lines. RESULTS Carrying GSTM1/GSTT1 double null genotype was found to be an independent risk factor for post-HSCT relapse in 86 children (adjusted HR: 6.52 [95% Cl, 2.76-15.42; p = 1.9 × 10-5]). BU-induced cell death preferentially in THP1GSTM1(non-null) and LCLsGSTM1(non-null) as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to null cells, while GSTT1 non-null cells showed increased baseline proliferation. CONCLUSION The clinical association suggests that GSTM1/GSTT1 double null genotype could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that GSTM1 status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation

Commentary: A myriad aberrations on information of ontogeny of drug metabolizing enzymes in the pediatric population: an obstacle for personalizing drug therapy in the pediatric population

Major lacunae exists in our understanding of how developmental changes in drug biotransformation influence drug's exposure and thus its efficacy and toxicity in children. It is not just about smaller weight in children, which modifies the pattern of the drug's exposure. There are developmental, functional changes in organ systems, liver to body mass ratios, changes in metabolism. Understanding these changes and conducting studies to obtain data on ontogeny of drug metabolizing enzymes is essential for implementation of personalized dosing schedules in the pediatric population

Molecular Dynamics simulation between human UGT2B10 and putative ligands used in pediatric busulfan-based conditioning regimens prior to hematopoietic stem cell transplantation (HSCT)

Abstract- Background Sinusoidal occlusion syndrome (SOS) is a life-threatening complication, arising from the overactivation of hepatic endothelial cells (1-3) after hematopoietic stem cell transplantation (HSCT). A genetic variant situated in the UGT2B10 gene (SNP ID: rs17146905) was associated with the occurrence of SOS (Hazard-ratio=4.7) by our research group (4). UDP-glucuronosyltransferases (UGTs) are crucial in drug metabolism. Prefered substrates of UGT2B10 include tertiary amines: Cotinine, amitriptyline, fluconazole, desloratadine, tamoxifen among other antidepressants, antifungals and chemotherapeutic drugs (6-7). - Hypothesis UGT2B10 may be implicated in the detoxification of hepatoxic molecules present during busulfan-based conditioning regimens prior to HSCT, influencing the level of exposure to potentially liver-threatening compounds - Methods 1. Human UGT2B10 model was obtained with the method of multiple-template homology modeling with MODELLER. 2. Interesting potential UGT2B10 substrates present during busulfan-based conditioning regimens prior to hematopoietic stem cell transplantation (HSCT) were selected based on clinical, chemical and biological criterias. 3. Docking predictions between the putative ligands and UGT2B10 were performed with AutoDock Vina. 4. Positive results, based on the results for the positive control, were selected for further Molecular Dynamics simulations with GROMACS. - Folder Content The folders contains the MD simulations results of 7 complexes, composed of UGT2B10, cofactor UDPGlcA, and putative substrates. A readme file comprising details of the file structure and nomenclature is also included. - References (1) Corbacioglu S. et al. Bone Marrow Transplant. 2018; 53(2):138-145 (2) Bonifazi F. et al. Front Immunol. 2020; 11:489 (3) Dalle et Giralt. Biol Blood Marrow Transplant. 2016; 22(3):400-409 (4) Ansari M. et al. Biol Blood Marrow Transplant. 2020; 26(5): (5) Izukawa et al. Drug Metab Dispos. 2009; 37(8):1759-1768 (6) Kaivosaari et al. Mol Pharmacol. 2007; 72(3):761-768 (7) Kato et al. Drug Metab Dispos. 2013; 41(7):1389-139

Developmental Pattern of Hepatic Drug‑Metabolizing Enzymes in Pediatric Population and its Role in Optimal Drug Treatment

Pediatric pharmacokinetics (PK) and pharmacodynamics (PD) differ from adults in multiple aspects. The extrapolation of PK/PD data from adults to children is not always simple because children are not small adults. Differential development of metabolic enzymes in children affects both PK and PD of a drug. Thus, the study of the developmental patterns of drug-metabolizing enzymes is essential to establish the PK and PD profile of drugs in the pediatric population. Further, these patterns may also aid to establish models for appropriate extrapolation of adult data for any newer drugs. We conducted a literature search on PubMed Central, Medline database, and Google Scholar with relevant search terms to obtain articles for this narrative review. The research on developing pattern of drug metabolizing enzymes is still evolving. This review presents an overview of the existing literature on developmental patterns of key metabolic enzymes in children. Greater emphasis needs to be given to study developmental pattern of metabolic enzymes as it not only helps drug development but also to optimize drug therapy in children

Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases

Glutathione S-transferases (GSTs) are detoxification enzymes involved in the metabolism of numerous chemotherapeutic drugs. Overexpression of GSTs is correlated with cancer chemotherapy resistance. One way to counter this phenotype is to use inhibitors. This protocol describes a method using a spectrophotometric assay to screen for potential GST inhibitors

Indo-Swiss symposium on advances in pharmacogenomic strategies for implementation of personalized medicine

The Indo–Swiss symposium on advances in pharmacogenomic strategies for implementation of personalized medicine was conducted as a part of the JIPMER Integrated Pharmacogenomics Program (JIPP), held in Puducherry, India on 23 November 2019. The symposium focused on the growing contribution of pharmacogenomic information in designing treatment strategies and promoting better approaches to personalized medicine. The primary objective of this symposium was to bridge gaps in understanding the basics and recent advances in the field of pharmacogenomics. This symposium sought to promote interaction between the Indian and Swiss researchers to initiate future collaborative research projects. This symposium also served as a platform for young researchers to present their research findings as posters to the audience