Sex Differences in Liver Toxicity—Do Female and Male Human Primary Hepatocytes React Differently to Toxicants In Vitro?

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 toxicants. We investigated whether sex-specific differences in acute hepatotoxicity can be observed in vitro at a cellular level by comparing hepatotoxic drug effects in male and female primary human hepatocytes. Significant sex-related differences were found for particular parameters and individual drugs showing that the tested substances are more toxic to female hepatocytes. Moreover, our work demonstrated that high content screening is feasible with pooled primary human hepatocytes in suspension.JRC.I.5-Systems Toxicolog