Production of reactive oxygen species due to metabolic activation of butylated hydroxyanisole.
The synthetic antioxidant butylated hydroxyanisole (BHA) stimulates superoxide formation in rat liver microsomes up to 10-fold. This stimulation is prevented by the monooxygenase inhibitor metyrapone and does not occur when NADH is consumed instead of NADPH indicating that metabolic activation is required for superoxide production. The BHA metabolite tert-butylhydroquinone (TBHQ) is much more active than BHA in stimulating superoxide production, and the amounts of TBHQ and formaldehyde formed from BHA in microsomes are sufficient to explain the effect of BHA. In buffer and in a xanthine oxidase system, superoxide production by TBHQ also takes place. TBHQ autoxidizes to tert-butylquinone (TBQ) and TBQ exceeds TBHQ by far in its capacity for superoxide production in microsomes. Thus, a 30-fold increase of basal superoxide production is induced by 5 microM TBQ. In rat forestomach, the target organ of BHA carcinogenicity in rodents, stimulation of superoxide production by BHA and more markedly by TBHQ and TBQ is also observed. Excess production of superoxide in microsomes by TBHQ is accompanied by excess production of hydrogen peroxide and of hydroxyl radicals. It is concluded that TBQ undergoes redox cycling leading to an oxidative burst in the presence of enzymes capable of one electron reduction of TBQ and that the BHA metabolite TBHQ enters the redox cycle by autoxidation. No oxygen activating properties can be ascribed to BHA itself.[1]References
- Production of reactive oxygen species due to metabolic activation of butylated hydroxyanisole. Kahl, R., Weinke, S., Kappus, H. Toxicology (1989) [Pubmed]
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