Rat urinary bladder hyperplasia induced by oral administration of carbonic anhydrase inhibitors.
The carbonic anhydrase inhibitors, acetazolamide and MK-0927, were given by oral route to male Sprague-Dawley rats at 200 mg/kg/day and 25 mg/kg/day, respectively, for up to 4 weeks. Sequential necropsies were performed and urinary bladders were examined by light microscopy (LM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Similar urinary bladder changes were seen with both compounds. SEM evidenced slight multifocal urothelial changes consisting of cell swelling, dissociation, degeneration, and exfoliation after 3 and 5 days of treatment. After 2 and 4 weeks of treatment, elevated or leafy microridges on the luminal cell surfaces were seen together with foci of swollen cells. After a 2-month-recovery-period, the urothelial surfaces were normal. LM and TEM showed multifocal vacuolation of the urothelium associated with inflammation of the underlying lamina propria after 3 and 5 days of treatment. Cellular hypertrophy and hyperplasia of the transitional epithelium was seen after a 5-day treatment, persisted without increasing severity after 2 and 4 weeks of treatment, and totally regressed after the recovery period. It was concluded that, in the rat urinary bladder, oral administration of acetazolamide and MK-0927 induced early degeneration and inflammation followed by epithelial regeneration, resulting in a reversible hyperplasia of the transitional epithelium.
Molon-Noblot
S
S
Department of Safety Assessment, Merck Sharp & Dohme-Chibret, Riom, France.
Boussiquet-Leroux
C
C
Owen
R A
RA
Irisarri
E
E
Durand-Cavagna
G
G
Peter
C P
CP
Duprat
P
P
D000086:Acetazolamide / Q000633:toxicity; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000633:toxicity*; D004848:Epithelium / Q000473:pathology; D006965:Hyperplasia / Q000139:chemically induced; D008297:Male; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000633:toxicity*; D013876:Thiophenes / Q000633:toxicity*; D001743:Urinary Bladder / Q000473:pathology*
D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; C057921:sezolamide; D000086:Acetazolamide