Effect of butylated hydroxyanisole added in vitro or administered to rats on N,N-dibutylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine metabolism by post-mitochondrial supernatant of liver homogenates.
The effect of butylated hydroxyanisole (BHA) on P-450-dependent omega-hydroxylation of N,N-dibutylnitrosamine (NDBA) to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), and the further oxidation of BBN to N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) by the alcohol/aldehyde dehydrogenase system was investigated using the post-mitochondrial supernatant of liver homogenates (S9) from acutely and chronically BHA pretreated animals or S9 fractions from untreated rats with BHA added. Acute oral BHA (50 and 250 mg.kg-1) did not change NDBA omega-oxidation, which was reduced by 35% only when the compound was administered 0.5% in the diet for 3 weeks. BCPN formation from BBN was unaffected by acute and chronic BHA pretreatment. In order to verify whether BHA or its metabolite(s) had a direct effect on NDBA and BBN oxidation, the compound was added to S9 fractions from untreated rats at various concentrations. Only when BHA concentrations were equimolar or in a 10-fold molar excess to the substrate concentration, we observed 30-50% inhibition of BBN formation and a reduced BCPN formation (60-80% of control values), from BBN. Thus, only at very high BHA concentrations could we confirm the inhibition of P-450-dependent mixed function oxidase and alcohol dehydrogenase activities involved in the metabolism of NDBA and BBN.
Pastorelli
R
R
Laboratory of Environmental Pharmacology and Toxicology, Istituto di Ricerche Farmacologiche, Mario Negri, Milano.
Ancidei
A
A
Benfenati
E
E
Fanelli
R
R
Airoldi
L
L
D000284:Administration, Oral; D000818:Animals; D002083:Butylated Hydroxyanisole / Q000494:pharmacology*; D002085:Butylhydroxybutylnitrosamine / Q000378:metabolism*; D002849:Chromatography, Gas; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D009602:Nitrosamines / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats
D009602:Nitrosamines; D002083:Butylated Hydroxyanisole; D002085:Butylhydroxybutylnitrosamine; C012279:dibutylnitrosamine; D003577:Cytochrome P-450 Enzyme System