title: Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects.
abstract: Sirolimus (SRL) and everolimus (EVR) are mammalian targets of rapamycin inhibitors (mTOR-I) largely employed in renal transplantation and oncology as immunosuppressive/antiproliferative agents. SRL was the first mTOR-I produced by the bacterium Streptomyces hygroscopicus and approved for several medical purposes. EVR, derived from SRL, contains a 2-hydroxy-ethyl chain in the 40th position that makes the drug more hydrophilic than SRL and increases oral bioavailability. Their main mechanism of action is the inhibition of the mTOR complex 1 and the regulation of factors involved in a several crucial cellular functions including: protein synthesis, regulation of angiogenesis, lipid biosynthesis, mitochondrial biogenesis and function, cell cycle, and autophagy. Most of the proteins/enzymes belonging to the aforementioned biological processes are encoded by numerous and tightly regulated genes. However, at the moment, the polygenic influence on SRL/EVR cellular effects is still not completely defined, and its comprehension represents a key challenge for researchers. Therefore, to obtain a complete picture of the cellular network connected to SRL/EVR, we decided to review major evidences available in the literature regarding the genetic influence on mTOR-I biology/pharmacology and to build, for the first time, a useful and specific "SRL/EVR genes-focused pathway", possibly employable as a starting point for future in-depth research projects.
authors.affiliation: Renal Unit, Department of Medicine, University/Hospital of Verona, 37126 Verona, Italy. simona.granata@univr.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Granata
authors.affiliation: Renal Unit, Department of Medicine, University/Hospital of Verona, 37126 Verona, Italy. alessandra.dallagassa@univr.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dalla Gassa
authors.affiliation: Liver Transplant Unit, Department of General Surgery and Odontoiatrics, University/Hospital of Verona, 37126 Verona, Italy. amedeo.carraro@ospedaleuniverona.it.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Carraro
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy. matteo.brunelli@ospedaleuniverona.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, University of Foggia, 71122 Foggia, Italy. giovanni.stallone@unifg.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stallone
authors.affiliation: Renal Unit, Department of Medicine, University/Hospital of Verona, 37126 Verona, Italy. antonio.lupo@univr.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lupo
authors.affiliation: Renal Unit, Department of Medicine, University/Hospital of Verona, 37126 Verona, Italy. gianluigi.zaza@univr.it.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zaza
mesh_terms: D000818:Animals; D000068338:Everolimus / Q000494:pharmacology*; D056726:Genetic Association Studies; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism; D010597:Pharmacogenetics; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: everolimus; genes; mTOR inhibitors; sirolimus; transplantation