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Free Radical-Derived Quinone Methide Mediates Skin Tumor

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Free Radical-Derived Quinone Methide Mediates Skin Tumor Proc. Natl. Acad. Sci. USA Vol. 88, pp. 946-950, February 1991 Medical Sciences Free radical-derived quinone methide mediates skin tumor promotion by butylated hydroxytoluene hydroperoxide: Expanded role for electrophiles in multistage carcinogenesis (chemical carcinogenesis/phenoxyl radicals/reactive intermediates/metabolic switching/ornithine decarboxylase) KATHRYN Z. GUYTON*, PURSHOTAM BHANt, PERIANNAN KUPPUSAMYt, JAY L. ZWEIER , MICHAEL A. TRUSH*, AND THOMAS W. KENSLER*§ *Division of Toxicological Sciences, Department of Environmental Health Sciences, tDepartment of Biochemistry, and tElectron Paramagnetic Resonance Laboratories, Department of Medicine, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205 Communicated by Paul Talalay, October 23, 1990 (receivedfor review September 25, 1990) ABSTRACT Free radical derivatives of peroxides, hydrop- tabolism of BHT in its actions as a promoter and toxin is eroxides, and anthrones are thought to mediate tumor promo- highlighted by the ability of several inhibitors of cytochrome tion by these compounds. Further, the promoting activity of P450 to suppress BHT toxicity (6, 7) and the observation that phorbol esters is attributed, in part, to their ability'to stimulate a hydroxylated metabolite is more effective than BHT as either the cellular generation of oxygen radicals. A hydroperoxide a tumor promoter or toxin in mouse lung (8, 9). Glutathione- metabolite of butylated hydroxytoluene, 2,6-di-tert-butyl4- depleting agents enhance liver and lung damage and elevate the hydroperoxyl4-methyl-2,5-cyclohexadienone (BHTOOH), has covalent binding of BHT in these tissues, suggesting that previously been shown to be a tumor promoter in mouse skin. toxicity may be mediated through an electrophilic intermediate (10, 11). Structure-activity studies of the 4-methyl position of BHTOOH is extensively metabolized by murine keratinocytes to BHT indicate that a quinone methide intermediate may be the several radical species. The primary radical generated from toxic electrophile (12). BHTOOH is a phenoxyl radical that can disproportionate to In a study of acute toxicities 2,6-di-tert-butyl-4-hydroper- form butylated hydroxytoluene quinone methide, a reactive oxyl-4-methyl-2,5-cyclohexadienone (BHTOOH), a hydro- electrophile. Since electrophilic species have not been previously peroxide metabolite of BHT, was demonstrated to be 18-fold postulated to mediate tumor promotion, the present study was more potent than the parent compound (13). Further, this undertaken to examine the role of this electrophile in the metabolite, in contrast with the parent compound, is a tumor promoting activity ofBHTOOH. The biological activities oftwo promoter in mouse skin (14), a tissue that apparently does not chemicalanalogs of BHTOOH, 4-trideuteromethyl-BHTOOH generate BHTOOH from BHT (unpublished observations). and 4-terl-butyl-BHTOOH, were compared with that of the BHTOOH is of particular interest because it undergoes parent compound. 4-Trideuteromethyl-BHTOOH and 4-tert- extensive metabolism in murine keratinocytes to form sev- butyl-BHTOOH have a reducedability or inability, respectively, eral free radical intermediates, including phenoxyl, peroxyl, to form a quinone methide; however, like the parent compound, alkoxyl, and alkyl radical derivatives (14). Considerable they both generate a phenoxyl radical when incubated with evidence suggests that free radicals and free radical-mediated keratinocyte cytosol. The potency of BHTOOH, 4-trideutero- processes are involved in the biochemical and biological methyl-BHTOOH, and 4-tert-butyl-BHTOOH as inducers of events of tumor promotion (15, 16), and the propensity of ornithine decarboxyiase, a marker of tumor promotion, was BHTOOH to generate free radicals may, therefore, be related commensurate with their capacity for generating butylated to its enhanced potency as a toxin and tumor promoter. hydroxytoluene quinone metbide. These initial results were The primary radical species generated from BHTOOH is confirmed in a two-stage tumor promotion protocol in female the BHT phenoxyl radical; this radical metabolite will readily SENCAR mice. Together, these data indicate that a quinone undergo disproportionation to regenerate the parent com- methide is mediating tumor promotion by BHTOOH, providing pound BHT with the concomitant production of 2,6-di-tert- direct evidence that an electrophilic intermediate can elicit this butyl-4-methylene-2,5-cyclohexadienone (BHT-QM), a reac- stage of carcinogenesis. tive electrophile (Fig. 1). Electrophiles have long been rec- ognized to play preeminent roles in the initiation of chemical Butylated hydroxytoluene (BHT; 2,6-di-tert-butyl4methyl- carcinogenesis through the covalent modification of nucleic phenol) has found wide commercial application because of its aci-ds (18). On the other hand, electrophilic species have not excellent antioxidant properties. Although BHT has attained previously been linked with tumor promotion. The present generally regarded as safe (GRAS) status as afood additive, this study was undertaken to probe the possible role ofBHT-QM, phenolic antioxidant has toxic as well as carcinogenicproperties a model electrophile, in this biological process. (1, 2). For example, BHT is toxic in both liver and lung and has been reported to increase tumorformation inthe progeny ofrats MATERIALS AND METHODS that had high lifetime feeding of BHT (3). BHT is also a weak Chemicals and Syntheses. BHT, 3,5-di-tert-butyl-hydroxy- hepatocarcinogen in male mice (4). The most notable carcino- benzoic acid, 2,4,6-tri-tert-butylphenol, LiAI[2Hh4, deuter- genic property of BHT, however, lies in its ability to act as a tumor promoter in a variety oftissues, including the liver, lung, Abbreviations: BHT, butylated hydroxytoluene (2,6-di-tert-butyl4 colon, bladder, and thyroid (5). BHT is known to be extensively methylphenol); [2H3]BHT, 2,6-di-tert-butyl-4-[aaa- 2H3]methyl- metabolized in its target tissues, and the toxic as well as phenol; BHTOOH, 2,6-di-tert-butyl-4-hydroperoxyl-4-methyl-2,5- tumor-promoting activities of BHT are thought to be mediated cyclohexadienone; [2H3]BHTOOH, 2,6-di-tert-butyl-44[a,aa-2H31- by metabolites of the parent compound. The role of the me- methyl-2,5-cyclohexadienone; t-Bu-BHTOOH, 2,4,6-tri-tert-butyl4 hydroperoxyl-2,5-cyclohexadienone; BHT-QM, 2,6,-di-tert-butyl4 methylene-2,5-cyclohexadienone; PMA, phorbol 12-myristate 13- The publication costs ofthis article were defrayed in part by page charge acetate; ODC, ornithine decarboxylase; EPR, electron paramagnetic payment. This article must therefore be hereby marked "advertisement" resonance. in accordance with 18 U.S.C. §1734 solely to indicate this fact. §To whom reprint requests should be addressed. 946 Downloaded by guest on September 30, 2021 Medical Sciences: Guyton et al. Proc. Natl. Acad. Sci. USA 88 (1991) 947 ated dioxane, and hematin as well as chemical solvents were treatment group of 1, 4, 8, 20, or 40 ,umol of hydroperoxide. obtained from Aldrich. 7,12-Dimethylbenz[a]anthracene was The compounds were dissolved in 200 ,Al of acetone and purchased from Sigma, and phorbol 12-myristate 13-acetate applied to the shaved dorsal skin ofmice in hair-growth-cycle (PMA) was supplied by LC Services (Woburn, MA). remission. At the time of maximal induction, 10 hr after L-[4CjOrnithine (56 uCi/mol; 1 Ci = 37 GBq) was from treatment, the animals were sacrificed, and the epidermis was Amersham/Searle. isolated. Tissue from two animals was pooled for generation 2,6-Di-tert-butyl-4-[a,a,a-2H3]methylphenol [2H3JBHT of the 12,000 x g epidermal supernatant. The ODC activity was synthesized by the method of Mizutani et al. (19). of this cytosol was subsequently determined in triplicate by 3,5-Di-tert-butyl-hydroxybenzoic acid was converted to the measuring the release of 14CO2 from L-[14C]ornithine by using methyl ester (melting point, 166-1670C), which was then an Eppendorf microvessel assay (24). Protein content was added to an excess of LiAl[2H14 in anhydrous ethyl ether. determined by using bovine serum albumin as a standard by After refluxing under nitrogen for 12 hr, the excess reagent the method of Bradford (25). was decomposed with sodium potassium tartrate (20). The Two-Stage Tumor Promotion Study. Two hundred SEN- precipitate was then removed, and the resulting solution w~s CAR female mice 7-9 weeks of age in the resting phase of washed, dried, and freed from solvent. Column chromatog- hair-growth cycle were initiated on the shaved dorsal skin raphy yielded [2H3]BHT, NMR (deuterated dioxane) 8 8.9 (s, with 20 nmol of7,12-dimethylbenz[a]anthracene dissolved in 2 H), 7.6 (s, 1 H), 3.4 (s, 18 H). BHT, [2H3]BHT, and 100 Al of acetone. The first stage of promotion was begun 10 2,4,6-tri-tert-butylphenol were oxidized by the method of days later and consisted of twice weekly treatments of 2 ,g Kharasch and Joshi (21), and the corresponding hydro- of PMA for 2 weeks. The mice were then randomly assigned peroxides were then recrystallized from hexane. NMR (deu- to eight second-stage promotion treatment groups of 25 mice terated dioxane) gave BHTOOH 6 12.1 (s, 1 H), 8.6 (s, 1 H), each. Twice weekly thereafter, the mice in each group were 3.3 (s, 3 H), 3.2 (s, 18 H); 2,6-di-tert-butyl-4-[a,a,a- exposed to their respective treatments dissolved in 200/4 of 2H3]methyl-2,5-cyclohexadieone ([2H3]BHTOOH) 6 12.1 (s, acetone and applied to the shaved dorsal skin. The treatment 1 H), 8.6 (s, 1 H), 3.2 (s, 18 H); and 2,4,6-tri-tert-butyl-4- groups included 8- and 20-Amol doses of each of the three hydroperoxyl-2,5-cyclohexadienone (t-Bu-BHTOOH) 812.1 hydroperoxides as well as an acetone-negative control and a (s, 1 H), 8.7 (s, 1 H), 3.2 (s, 18 H), 2.9 (s, 9 H). BHTOOH and PMA-positive control. Treatment continued for a total of 24 [2H3]BHTOOH were determined to be >99% pure from other weeks of first- and second-stage promotion.
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