title: Sex differences in liver toxicity-do female and male human primary hepatocytes react differently to toxicants in vitro?
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.
authors: Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Ispra, Varese, Italy.
authors: Milena
authors: M
authors: Mennecozzi
authors: Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Ispra, Varese, Italy.
authors: Brigitte
authors: B
authors: Landesmann
authors: Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Ispra, Varese, Italy.
authors: Taina
authors: T
authors: Palosaari
authors: Center for Alternatives to Animal Testing, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America.
authors: Georgina
authors: G
authors: Harris
authors: Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Ispra, Varese, Italy.
authors: Maurice
authors: M
authors: Whelan
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D002110:Caffeine / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000633:toxicity; D004008:Diclofenac / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009853:Omeprazole / Q000633:toxicity; D061251:Primary Cell Culture; D012727:Sex Characteristics; D014700:Verapamil / Q000633:toxicity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D000082:Acetaminophen; D002110:Caffeine; D014700:Verapamil; D009853:Omeprazole; D002118:Calcium; D002746:Chlorpromazine