Alpha 2u-globulin nephropathy without nephrocarcinogenesis in male Wistar rats administered 1-(aminomethyl)cyclohexaneacetic acid.
Alpha 2u-Globulin (alpha 2u) nephropathy is a male rat-specific condition caused by a diverse group of xenobiotics. Features of this nephropathy include hyaline droplet accumulation in proximal tubules, tubular epithelial necrosis and regeneration, exacerbation of spontaneous renal disease, and induction of renal epithelial tumors. Nephrocarcinogenicity of compounds that cause this nephropathy may be a consequence of increased proximal tubular proliferation resulting from cell injury. These studies document alpha 2u nephropathy without primary renal epithelial tumors in male Wistar rats administered 1-(aminomethyl)cyclohexaneacetic acid (gabapentin), a therapeutic agent with antiepileptic/anticonvulsant properties. In a series of preclinical studies gabapentin was administered to rats at the following doses and durations: 50 and 2000 mg/kg for 2 weeks; 250, 1000, 2000, and 3000 mg/kg for 13 weeks; 250, 1000, and 2000 mg/kg for 52 and 104 weeks. Renal effects were evaluated by biochemical, immunocytochemical, histopathologic, and ultrastructural techniques. Reversible increases in size and distribution of hyaline droplets within proximal tubular epithelium occurred through 1 year of treatment at a severity that was dose-dependent. In males given 2000 mg/kg, alpha 2u accumulation, degeneration, and necrosis of the P2 segment and intraluminal cellular casts were seen after 2 days of treatment. In the 2-week study, the size and number of phagolysosomes containing alpha 2u and the renal tissue alpha 2u increased with increasing dose and time. By Day 7, polymorphic crystalline inclusions were abundant in phagolysosomes of 2000 mg/kg males. In subchronic and chronic studies, spontaneous glomerulonephrosis was exacerbated in males given 2000 mg/kg, and, interestingly, no drug-related effect on renal tumor incidence was observed. To the best of our knowledge, this is the first documentation of the absence of nephrocarcinogenic effect in male rats treated for up to 104 weeks with a compound that causes acute and chronic lesions of alpha 2u nephropathy.
Dominick
M A
MA
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, Michigan 48105.
Robertson
D G
DG
Bleavins
M R
MR
Sigler
R E
RE
Bobrowski
W F
WF
Gough
A W
AW
D000085:Acetates / Q000633:toxicity*; D000510:Alpha-Globulins / Q000302:isolation & purification / Q000652:urine*; D000588:Amines; D000818:Animals; D002850:Chromatography, Gel; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077206:Gabapentin; D005921:Glomerulonephritis / Q000139:chemically induced; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000139:chemically induced; D007687:Kidney Tubules, Proximal / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D009929:Organ Size; D051381:Rats; D011919:Rats, Inbred Strains; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000510:Alpha-Globulins; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; C013803:alpha 2u globulin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin