PT  - JOURNAL ARTICLE
AU  - Céline Parmentier
AU  - Germaine L. Truisi
AU  - Konrad Moenks
AU  - Sven Stanzel
AU  - Arno Lukas
AU  - Annette Kopp-Schneider
AU  - Eliane Alexandre
AU  - Philip G. Hewitt
AU  - Stefan O. Mueller
AU  - Lysiane Richert
TI  - Transcriptomic Hepatotoxicity Signature of Chlorpromazine after Short- and Long-Term Exposure in Primary Human Sandwich Cultures
AID  - 10.1124/dmd.113.052415
DP  - 2013 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1835--1842
VI  - 41
IP  - 10
4099  - http://dmd.aspetjournals.org/content/41/10/1835.short
4100  - http://dmd.aspetjournals.org/content/41/10/1835.full
SO  - Drug Metab Dispos2013 Oct 01; 41
AB  - Drug-induced liver injury is the most frequent reason for market withdrawal of approved drugs, and is difficult to predict in animal models. Here, we analyzed transcriptomic data derived from short- and long-term cultured primary human hepatocytes (PHH) exposed to the well known human hepatotoxin chlorpromazine (CPZ). Samples were collected from five PHH cultures after short-term (1 and 3 days) and long-term (14 days) repeat daily treatment with 0.1 or 0.2 µM CPZ, corresponding to Cmax. Two PHH cultures were additionally treated with 1 µM CPZ, and the three others with 0.02 µM CPZ. Differences in the total number of gene changes were seen between donors and throughout treatment. Specific transcriptomic hepatotoxicity signatures were created for CPZ and consisted of inflammation/hepatitis, cholestasis, and liver proliferation in all five donors, as well as fibrosis and steatosis, which were observed in four of five donors. Necrosis was present in three of five donors, and an indicative signature of cirrhosis was observed after long-term 14-day repeat treatment, also in three of five donors. The inter-donor variability in the inflammatory response to CPZ treatment was associated with variability in the strength of the response of the transcriptomic hepatotoxicity signatures, suggesting that features of inflammation could be related to the idiosyncratic hepatotoxic effects of CPZ in humans.