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 pha...

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Bibliographic Details
Published in:PloS one 2015-04, Vol.10 (4), p.e0122786
Main Authors: Mennecozzi, Milena, Landesmann, Brigitte, Palosaari, Taina, Harris, Georgina, Whelan, Maurice
Format: Article
Language:English
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
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0122786