Metabolism and disposition of bladder carcinogens in rat and guinea pig: possible mechanism of guinea pig resistance to bladder cancer.
The metabolism and disposition of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) were studied in rat and guinea pig. Rat is susceptible whereas guinea pig is resistant to FANFT-induced bladder cancer. Rats and guinea pigs were p.o. administered either 2-[14C]ANFT or 2-[14C]FANFT (100 mg/kg), and 18-h urine and feces were collected. Tissue distribution of radiolabel was determined. In both species, the highest concentrations of radioactivity expressed as nmol/g tissue were observed in the urine and intestines. Urinary metabolites were separated by high-performance liquid chromatography and radioactivity determined by radioanalytical detection. FANFT was not detected in urine from either species under any experimental condition. More ANFT was observed in urine following FANFT than ANFT administration. This deformylation-dependent excretion of FANFT was demonstrated in both species and has been previously described as renal metabolic/excretory coupling. Less ANFT, the carcinogen more proximate than FANFT, is excreted in guinea pigs compared with rats. A unique ANFT metabolite was identified in guinea pig but not rat urine. This metabolite represented 80 and 18% of radioactivity recovered in guinea pig urine following ANFT and FANFT administration, respectively. A metabolite produced by guinea pig liver and kidney microsomes in the presence of uridine-5'-diphosphoglucuronic acid coeluted with this unique metabolite. The urinary metabolite was characterized using hydrolytic enzymes, acid hydrolysis, and mass spectrometry and identified as an ANFT-N-glucuronide. A unique UDP-glucuronosyl-transferase appears to be responsible, at least in part, for the reduced amount of free ANFT excreted by guinea pigs compared with rats. Reduced levels of urinary ANFT observed in guinea pigs may partially explain the resistance of this species to FANFT-induced bladder cancer.
Dawley
R M
RM
Geriatric Research, Education, and Clinical Center, Veterans Administration Medical Center, St. Louis, MO 63125.
Zenser
T V
TV
Mattammal
M B
MB
Lakshmi
V M
VM
Hsu
F F
FF
Davis
B B
BB
D000818:Animals; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000378:metabolism*; D004198:Disease Susceptibility; D005200:FANFT / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D014018:Tissue Distribution; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*
D002250:Carbon Radioisotopes; D002273:Carcinogens; C024885:ANFT; D005200:FANFT; D014453:Glucuronosyltransferase