Gabapentin-induced mitogenic activity in rat pancreatic acinar cells.
Gabapentin induces pancreatic acinar cell tumors in rats through unknown, yet apparently nongenotoxic mechanisms. The primary objective of this study was to determine whether gabapentin acts as a tumor promoter by stimulating acinar cell proliferation in rat pancreas. To this end, indices of pancreatic growth, including increased pancreatic weight, stimulation of acinar cell proliferation, and/or enhanced expression of immediate-early oncogenes were monitored in rats given gabapentin in the diet at 2 g/kg/day for up to 12 months. Rats fed raw soy flour (RSF), a known inducer of pancreatic acinar cell tumors through cholecystokinin-mediated mitogenic stimulation, were used throughout as positive controls. In addition, recent data suggests that gabapentin binds to the alpha(2)delta subunit of a voltage-gated, L-type calcium channel. Because signaling pathways for proliferative processes in pancreatic acinar cells involve intracellular calcium mobilization, the effects of gabapentin on intracellular calcium mobilization ([Ca(2+)](i)) and (3)H-thymidine incorporation were investigated in pancreatic acinar cells isolated from normal rat pancreas and in the AR42J rat pancreatic tumor cell line. As indicated by BrdU labeling indices, acinar cell proliferation increased 3-fold by Day 3 of RSF treatment and remained slightly greater than controls throughout the experiment. Pancreatic weights of RSF-fed rats were 32 to 56% greater than controls throughout the experiment. In contrast, gabapentin had no effect on pancreatic weight or acinar cell labeling index, and therefore had no apparent effect on pancreatic growth. In isolated pancreatic acinar cells, however, gabapentin induced mobilization of intracellular calcium and caused a slight increase in (3)H-thymidine incorporation. The data suggest that gabapentin may possess low level mitogenic activity, which is not easily detectable in in vivo assays.
Dethloff
L
L
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. lloyd@dethloff@wl.com
Barr
B
B
Bestervelt
L
L
Bulera
S
S
Sigler
R
R
LaGattuta
M
M
de La Iglesia
F
F
D000085:Acetates / Q000633:toxicity*; D000588:Amines; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D000077206:Gabapentin; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017781:Genes, Immediate-Early; D008934:Mitogens / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D008934:Mitogens; D011949:Receptors, Cholecystokinin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D002118:Calcium