Effect of acute and chronic butylated hydroxyanisole administration on in vivo glucuronidation of N-nitrosobutyl(4-hydroxybutyl)amine in rats.
The urinary metabolic pattern of N-nitrosobutyl(4-hydroxybutyl)amine (NB4HBA) administered ip at a dose of 5 mg/kg body weight was studied in animals either pretreated with butylated hydroxyanisole (BHA) as a single oral dose of 50 or 250 mg/kg, or fed a diet containing 0.1 or 0.5% BHA. The 24-hr urinary excretion of NB4HBA, its glucuronic acid-conjugate (NB4HBA-G) and N-nitrosobutyl(3-carboxypropyl)amine (NB3CPA) in control rats were 0.12, 0.75 and 30% of the administered dose, respectively, and were not changed after a single oral dose of 50 mg BHA/kg. NB4HBA-G was significantly reduced in the urine of rats given 250 mg BHA/kg. In vitro assays carried out using rat-hepatic microsomal preparations as the source of the enzyme UDP-glucuronyl transferases (GT) and NB4HBA as the substrate, suggest that a competition between NB4HBA and BHA for the same enzyme may be the cause of the decreased NB4HBA-G excretion observed in vivo. A fourfold increase in NB4HBA-G urinary excretion was observed after chronic 0.5% BHA feeding; moreover, the glucuronic acid-conjugate of NB3CPA (NB3CPA-G), which was not detected in the controls or after acute BHA treatment, appeared in the urine of rats given dietary BHA for 3 wk, accounting for about 10% of the administered NB4HBA. In vitro experiments indicate that the increased glucuronides excretion may be the result of an elevated hepatic GT activity.
Pastorelli
R
R
Laboratory of Environmental Pharmacology and Toxicology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Ancidei
A
A
Fanelli
R
R
Airoldi
L
L
D000818:Animals; D002083:Butylated Hydroxyanisole / Q000008:administration & dosage / Q000633:toxicity*; D002085:Butylhydroxybutylnitrosamine / Q000031:analogs & derivatives / Q000652:urine*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009602:Nitrosamines / Q000652:urine*; D051381:Rats
D009602:Nitrosamines; D002083:Butylated Hydroxyanisole; D002085:Butylhydroxybutylnitrosamine; C051500:N-nitrosobutyl-N-(4-hydroxybutyl)amine glucuronide