Electronic and structural requirements for metabolic activation of butylated hydroxytoluene analogs to their quinone methides, intermediates responsible for lung toxicity in mice.
Previous studies have shown that butylated hydroxytoluene (BHT) undergoes oxidation by cytochrome P450 to form BHT-quinone methide. BHT-quinone methide is probably responsible for BHT-induced lung damage in mice. In this study, we calculated the MO parameters for BHT analogs and the corresponding quinone methide intermediates. Except for the analogs with structures that form a highly sterically hindered quinone methide, correlations could be established between the lung toxicity in mice and electronic charges on the hydroxyl oxygen and 4-carbon atoms of BHT analogs. The same toxicity could also be correlated to the difference between the heat of formation of the quinone methide intermediates and the parent BHT analogs, and to the electronic charge on the carbonyl oxygen atom of the quinone methides. These results suggest that the metabolic activation of BHT analogs to their quinone methide intermediates is energetically dependent on the oxidation of the aromatic pi-electron system, and that the toxic potency of BHT analogs is controlled by protonation of the oxygen atom of the quinone methides. These electronic features provide further evidence of the importance of the quinone methide intermediates in the mechanism of lung toxicity induced by BHT analogs.
Yamamoto
K
K
Department of Chemistry, Hokuriku University, Kanagawa-machi, Kanazawa, Japan.
Kato
S
S
Tajima
K
K
Mizutani
T
T
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D001711:Biotransformation; D002084:Butylated Hydroxytoluene / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D045563:Indolequinones; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D008168:Lung / Q000187:drug effects*; D051379:Mice; D011809:Quinones / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000975:Antioxidants; D045563:Indolequinones; D007211:Indoles; D011809:Quinones; C068040:quinone methide; D002084:Butylated Hydroxytoluene