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.