HLA Driven, Dose Dependence of Flucloxicillin, Pazopanib and Carbenicllin on Hepatotoxicity

Abstract

The liver is a fundamental organ that is responsible for metabolism and excretion of drugs and is therefore exposed to drug-induced liver injury (DILI). This study was conducted to understand DILI when exposed to Carbenicillin (CBN), Flucloxicillin (FLX) and Pazopanib (PZP) using in vitro and in vivo models; and to establish an in vitro HLA B*57:01 gene transfected cell line model to study idiosyncratic DILI. 1) DILI upon drug exposure was tested in vitro using Hep 1C1C7 cell line by looking at cell growth, morphology, percent cell viability and IC50 of cell growth inhibition, followed by measuring the expression of biomarker proteins Hmgb1, S100a9, Nrf2 and AKR1b10 in primary hepatocytes. 2) In vivo effects of FLX on liver injury were studied by measuring alanine aminotransferase (ALT) levels in FLX treated transgenic mouse serum. The results from in vitro work showed a concentration dependent DILI upon FLX and PZP treatment, demonstrated by reduction in cell count and percent cell viability. However, no change in the release of stress biomarkers was observed in drug treated primary hepatocytes. In the in vivo studies FLX treated and control mice showed no difference in the expression of ALT levels. The HLA B*57:01 gene transfected Hep 1C1C7 cell line did not express the gene of interest making it unsuitable to study HLA linked idiosyncratic DILI. The differences in the observations from in vitro and in vivo work of this project along with future directions are discussed in this work.