Title

 

Authors

D. Strobbe^1,2,3
Doctorate School in Molecular and Cellular Pharmacology
¹ Dep of Pharmacology and Anesthesiology,University of Padova
² Dep of Experimental Evolutionary Biology, University of Bologna
³ Dep of Neurological Scinces, Univesrity of Bologna

 

Abstract

Pharmacogenomics deals with the influence of genetic variation on drug response in patients and it can be study by correlating gene expression or single-nucleotide polymorphisms (SNPs) with a drug’s efficacy or toxicity. Using this connection, many studies describe the role of nuclear DNA (nDNA) in drugs toxicity. Despite the mitochondrial genome (mtDNA), which is present as nuclear genome in all human cells, might also have a role in drugs toxicity, no data is available. We propose to complete the scanning of human genome by investigating the genetic variation of mtDNA, which indeed could explain the appearance of drug side effect. The experimental model is a prerequisite of this investigation, therefore the first step was the collection of a wide cohort of control transmitochondrial cell hybrids (cybrids), harboring the common SNPs that characterize the Caucasian haplogroups (H, J, T, U, K, N). Cytoplasmatic hybrids, obtained by fusion of enucleated fibroblasts from healthy donor with osteosarcoma cells deprived of mtDNA (rho0), give the opportunity to investigate the influence of mtDNA polymorphism without the influence of the donor nuclear genome. In the present year thesequencing analysis of mtDNA will be applied to identify the haplogroups of fibroblast and to confirm its persistence in cybrids. Only selected cybrids will be used as in vitro models for studies to possibly demonstrate correlation among side effects of antibiotics, antiepileptic, statins, antineoplastic and neurotoxic drugs and mtDNA haplogroup. The pharmacological response will be measured by different markers of respiratory chain (OXPHOS) activity in cybrids incubated in experimental oxidative stress condition (es. glucose free-galactose medium).