Enhanced lung toxicity of butylated hydroxytoluene in mice by coadministration of butylated hydroxyanisole.

The ip coadministration of 200 mg/kg butylated hydroxyanisole (BHA) with a subtoxic dose (200 mg/kg) of butylated hydroxytoluene (BHT) enhanced the lung toxicity of BHT in mice. BHA coadministration significantly increased the radioactivity covalently bound to lung macromolecules at 4-8 hr after [14C]BHT. The area under the concentration versus time curve (AUC) for unchanged BHT in the lung for 24 hr after the coadministration was about 140% of that after the sole administration of BHT. At 2-8 hr after BHT, the coadministration produced a 40-85% increase in plasma concentration of unchanged BHT, but a 40-60% decrease in plasma concentration of total BHT (mainly consisted of BHT metabolites). The total metabolism of BHT by liver 9000 g supernatant was significantly reduced by in vitro addition of BHA. Pretreatment of mice with 200 mg/kg BHA also reduced the rate of 9000 g supernatant metabolism of BHT. These results support the suggestion that coadministration of BHA and BHT results in a decrease in the first-pass metabolism of BHT in the liver and thus the lung is exposed to a larger amount of BHT, developing enhanced toxic response.