Differential responses of human hepatocytes to the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine.
Nevirapine is a non-nucleoside reverse transcriptase (RT) inhibitor used for the treatment of AIDS and the prevention of mother-to-child transmission of HIV-1. Despite its therapeutic benefits, treatment with nevirapine has been associated with significant incidences of liver and dermal toxicity. The present study examined the effects of nevirapine on cell growth and death in human hepatocyte HepG2 cells and THLE2 cells and the possible pathways involved in these effects. The concentrations of nevirapine inhibiting 50% cell growth were similar for both cell lines. Nevirapine (0-250 µM) treatment caused a slight increase in the amount of lactate dehydrogenase released into the medium. Apoptotic cell death did not contribute to the decrease in viable cells. Exposing of HepG2 cells to nevirapine caused G2/M phase arrest, and the activity of senescence-associated β-galactosidase was not altered. In THLE2 cells, the percentage of cells in G1/G0 phase was increased and cellular senescence was induced in a concentration-dependent manner. Endogenous non-telomeric RT activity was not detected in either cell line. Western blot analysis indicated lower levels of p53 and phospho-p53 (ser15) in HepG2 cells as compared to THLE2 cells; no significant changes in p53 or phospho-p53 (ser15) were noted with nevirapine treatment. These data demonstrate that nevirapine inhibits cell growth, induces cell cycle arrest at different phases, and has different effects on cellular senescence in HepG2 cells and THLE2 cells. The differential responses appear to be related to differences in the basal levels of p53 in the HepG2 cells and THLE2 cells.
Division of Biochemical Toxicology, National Center for Toxicological Research, USA.
Jia-Long
JL
Fang
Frederick A
FA
Beland
D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D048708:Cell Growth Processes / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019829:Nevirapine / Q000633:toxicity*; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018894:Reverse Transcriptase Inhibitors; D016159:Tumor Suppressor Protein p53; D019829:Nevirapine