Abstract
There is increasing amount of evidence for sex variation in drug efficiency and toxicity profiles. Women are more susceptible than men to acute liver injury from xenobiotics. In general, this is attributed to sex differences at a physiological level as well as differences in pharmacokinetics and pharmacodynamics, but neither of these can give a sufficient explanation for the diverse responses to xenobiotics. Existing data are mainly based on animal models and limited data exist on in vitro sex differences relevant to humans. To date, male and female human hepatocytes have not yet been compared in terms of their responses to hepatotoxic drugs. We investigated whether sex-specific differences in acute hepatotoxicity can be observed in vitro by comparing hepatotoxic drug effects in male and female primary human hepatocytes. Significant sex-related differences were found for certain parameters and individual drugs, showing an overall higher sensitivity of female primary hepatocytes to hepatotoxicants. Moreover, our work demonstrated that high content screening is feasible with pooled primary human hepatocytes in suspension.
Highlights
There are marked sex-based differences in the epidemiology, clinical manifestations, progression and treatment of disease, as well as pharmacodynamics, -kinetics, and adverse drug effects
Diclofenac-induced hepatocyte injury is typically associated with an acute hepatitis-like histology involving necrosis, in some cases mixed hepatocellular cholestatic injury, and mediated by acyl glucuronide covalent binding with cellular proteins, oxidative stress, mitochondrial permeability transition and mitochondrial damage [37] [38]
We investigated the mechanisms underlying the cytotoxic effects of Diclofenac, Chlorpromazine, Acetaminophen, Verapamil, and Omeprazole by measuring changes in nuclear intensity (Hoechst 33342 dye), reactive oxygen species (ROS) accumulation (DHE dye), mitochondrial damage (TMRE dye), plasma membrane permeability modification (TOTO3 dye), calcium accumulation (Fluo-4 dye), and endoplasmic reticulum status (ER tracker red) in pooled primary hepatocytes
Summary
There are marked sex-based differences in the epidemiology, clinical manifestations, progression and treatment of disease, as well as pharmacodynamics, -kinetics, and adverse drug effects. These differences are derived from the fundamental biological differences between sexes and are only partially understood in molecular and cellular terms [1]. Males are preferred because they are thought to be less variable due to their constant hormone levels. This variability should not be ignored as hormones can play a role in many inflammatory responses [5] [6]
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