Detoxifying potential of thioproline against N-nitroso compounds, N-nitrosodimethylamine and N-nitrosocimetidine.
Thioproline (TPRO), an effective nitrite trapping agent in vivo, was examined for its detoxifying ability in rats against N-nitrosodimethylamine (NDMA) and N-nitrosocimetidine (NCIM). When NDMA (37-101.5 mg/kg) was administered with TPRO (532 mg/kg), no influence of TPRO on NDMA-induced lethality and histological results in liver were observed. NDMA oxygenase activity measured by formaldehyde formation was not affected either. Denitrosation is a route of detoxication of N-nitroso compounds. When NCIM (100 mg/kg), a direct acting mutagen but not carcinogen, was given by gavage with TPRO, urinary excretion of N-nitrosothioproline (NTPRO) in rats apparently increased compared with TPRO alone. This result shows that TPRO is a trapping agent in vivo for nitrosating (NO) species originating from N-nitroso compounds, e.g., NCIM, which are denitrosated non-enzymatically in stomach acidic conditions. Transnitrosation from NDMA to TPRO, where enzymatic denitrosation is required, did not occur in measurable amount after oral administration of NDMA and TPRO.
Frank
N
N
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg.
Tsuda
M
M
Ohgaki
H
H
Frei
E
E
Kato
T
T
Sato
S
S
D000818:Animals; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1; D004128:Dimethylnitrosamine / Q000378:metabolism* / Q000633:toxicity; D005557:Formaldehyde / Q000378:metabolism; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009603:Nitroso Compounds / Q000652:urine*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine*; D053778:Thiazolidines
D009603:Nitroso Compounds; D013844:Thiazoles; D053778:Thiazolidines; D005557:Formaldehyde; C019503:nitrosocimetidine; D002927:Cimetidine; C039001:N-nitrosothioproline; C003438:thiazolidine-4-carboxylic acid; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D004128:Dimethylnitrosamine