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Acetaminophen induces a reversible switch from rough to smooth endoplasmatic reticulum and leads to glycogen degradation in human hepatocytes
Author(s) -
Ullrich Anett,
Stolz Donna Beer,
Ellis Ewa C.,
Strom Stephen C.,
Michalopoulos George K.,
Berg Christine,
Hengstler Jan G.,
Runge Dieter
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a189
Subject(s) - acetaminophen , hepatocyte , glycogen , albumin , chemistry , urea , in vitro , pharmacology , drug , biochemistry , biology
Human hepatocytes are the in‐vitro system of choice to study drug‐induced processes in man. We have developed and validated HEPAC 2 : a serum‐free long‐term culture system for human hepatocytes. Cellular viability and liver functions (urea and albumin production) were monitored daily. These functions remained relatively constant for up to 3 weeks. We used HEPAC 2 to study the effects of repetitive drug treatments on hepatocellular functions and morphology. Acetaminophen (APAP) was used as a model substance. Hepatocytes were exposed to 18.6 mM APAP for 24 h. Subsequently, culture medium was replaced by medium without APAP and the same exposure scenario was repeated every 4 days. During APAP treatment urea and albumin secretion were reversible reduced by 15–30% and 70–80%. Cytochrome P450 2E1 and 1A2 were active for at least 3 weeks, since cellular response to APAP did not change during the first 4–5 cycles of exposure to APAP. Electron microscopy revealed that APAP led to a complete replacement of rough ER by smooth ER and degradation of glycogen. After removal of APAP, hepatocytes refilled their glycogen stores within 1 day, while it took about 2–3 days for complete regeneration of rough ER. These data demonstrate the suitability of HEPAC 2 to serve as a tool for repetitive screening of drug‐mediated changes on hepatocyte functions. Furthermore, it may help to overcome the sparse availability of human hepatocytes for testing drug‐mediated responses in man.