Studies on the mechanism of enhancement of butylated hydroxytoluene-induced mouse lung toxicity by butylated hydroxyanisole.
The studies described in this report were designed to probe possible mechanisms whereby butylated hydroxyanisole (BHA) is able to enhance butylated hydroxytoluene (BHT)-induced mouse lung toxicity. In experiments with mouse lung slices, BHA enhanced the covalent binding of BHT to protein, indicating that the interaction between BHA and BHT takes place in the lung. Subcutaneous administration of either BHA (250 mg/kg) or diethyl maleate (DEM, 1 ml/kg) to male CD-1 mice produced a similar enhancement of BHT-induced lung toxicity. In contrast to DEM, the administration of BHA (250 or 1500 mg/kg) did not decrease mouse lung glutathione levels, suggesting that the effect of BHA is not due to the depletion of glutathione levels. We previously observed that in the presence of model peroxidases a unique interaction occurs between BHA and BHT, resulting in the increased metabolic activation of BHT. Upon the addition of hydrogen peroxide or various hydroperoxides to mouse lung microsomes, BHA significantly increased the covalent binding of BHT to protein. BHA also stimulated the rate of formation of hydrogen peroxide by 4.7-fold in mouse lung microsomes. Likewise, hydrogen peroxide resulting from the NADPH cytochrome P-450 (c) reductase-catalyzed redox cycling of tert-butylhydroquinone, a microsomal metabolite of BHA, supported the peroxidase-dependent BHA-enhanced formation of BHT-quinone methide. These results suggest that BHA could facilitate the activation of BHT in the lung as a result of both the increased formation of hydrogen peroxide and the subsequent peroxidase-dependent formation of BHT-quinone methide from the direct interaction of BHA with BHT.
Thompson
D C
DC
Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland 21205.
Trush
M A
MA
D000818:Animals; D002083:Butylated Hydroxyanisole / Q000494:pharmacology*; D002084:Butylated Hydroxytoluene / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D006873:Hydroquinones / Q000378:metabolism; D008168:Lung / Q000187:drug effects*; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D010084:Oxidation-Reduction; D011809:Quinones / Q000378:metabolism
D006873:Hydroquinones; D008298:Maleates; D011809:Quinones; D002084:Butylated Hydroxytoluene; D002083:Butylated Hydroxyanisole; C024709:2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone; C018855:2-tert-butylhydroquinone; C014476:diethyl maleate; D005978:Glutathione