Sex differences in liver toxicity-do female and male human primary hepatocytes react differently to toxicants in vitro?

• Published in: PloS one Vol. 10; no. 4; p. e0122786
• Main Authors: Mennecozzi, Milena, Landesmann, Brigitte, Palosaari, Taina, Harris, Georgina, Whelan, Maurice
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.04.2015; Public Library of Science (PLoS)
• Subjects: Acetaminophen - toxicity; Analysis; Animal models; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Caffeine - toxicity; Calcium - metabolism; Cell Membrane Permeability - drug effects; Cell Survival - drug effects; Cells, Cultured; Chlorpromazine - toxicity; Diclofenac - toxicity; Dose-Response Relationship, Drug; Drugs; Endoplasmic Reticulum - drug effects; Female; Gender aspects; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - physiology; Hepatotoxicity; Humans; Liver; Liver diseases; Male; Membrane Potential, Mitochondrial - drug effects; Omeprazole - toxicity; Parameter sensitivity; Pharmacodynamics; Pharmacokinetics; Pharmacology; Primary Cell Culture; Sex; Sex Characteristics; Sex differences; Toxicants; Toxicity; Verapamil - toxicity; Xenobiotics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0122786

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.