title: Role of quinone methide in the in vitro toxicity of the skin tumor promoter butylated hydroxytoluene hydroperoxide.
abstract: An electrophilic quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone, BHT-QM) functions in the toxicity of butylated hydroxytoluene (BHT) in both rodent liver and lung. BHT-QM has also been demonstrated to mediate tumor promotion in mouse skin by another metabolite of BHT, 2,6-di-tert-butyl-4-hydroperoxy-4-methyl-2,5-cyclohexadienone (BHTOOH). In the present study, the role of BHT-QM in the cytotoxicity of BHTOOH was investigated. The toxicity of BHTOOH was potentiated by glutathione depletion and inhibited by thiol compounds, indicating that BHTOOH is activated to a thiol-reactive, toxic intermediate. This activation process was suggested to be iron-dependent by the ability of an Fe(III)-specific chelator to inhibit BHTOOH toxicity. Comparative study of analogs of BHTOOH in which the 4-methyl group was substituted with CD3, ethyl, isopropyl or tert-butyl supported the hypothesis that BHT-QM mediates this toxicological response. The decreased rate of reactivity of quinone methides that occurs as the 4-alkyl group is enlarged was accompanied by a corresponding reduction in toxic potency. The structural requirements for quinone methide toxicity were also explored with a series of BHTOOH analogs substituted at the 2- and 6-positions of the molecule. Reducing the lipophilicity of the 2,6-tert-butyl groups is known to increase quinone methide reactivity with glutathione but does not diminish the rate of quinone methide formation from the hydroperoxide. Interestingly, alteration of only one of the tert-butyl groups did not change the toxic potency, whereas removal or replacement of both tert-butyl groups dramatically reduced the toxicity in control cells but not glutathione-depleted cells.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205.
authors.forename: K Z
authors.initials: KZ
authors.lastname: Guyton
authors.forename: J A
authors.initials: JA
authors.lastname: Thompson
authors.forename: T W
authors.initials: TW
authors.lastname: Kensler
mesh_terms: D000818:Animals; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives* / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002614:Chelating Agents / Q000494:pharmacology; D003043:Cocarcinogenesis; D003124:Colorimetry; D003676:Deferoxamine / Q000494:pharmacology; D045563:Indolequinones; D007211:Indoles / Q000633:toxicity*; D051379:Mice; D008854:Microscopy, Electron; D010545:Peroxides / Q000633:toxicity*; D011809:Quinones / Q000633:toxicity*; D012878:Skin Neoplasms / Q000139:chemically induced*; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles; D014343:Trypan Blue; D014407:Tumor Cells, Cultured
chemical_list: D002273:Carcinogens; D002614:Chelating Agents; D045563:Indolequinones; D007211:Indoles; D010545:Peroxides; D011809:Quinones; D013778:Tetrazolium Salts; D013844:Thiazoles; C068040:quinone methide; D002084:Butylated Hydroxytoluene; C046508:2,6-di-tert-butyl-4-hydroperoxy-4-methyl-2,5-cyclohexadienone; C022616:thiazolyl blue; D014343:Trypan Blue; D003676:Deferoxamine