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Production of a Highly Reactive Alkylating Agent from the Organospecific Carcinogen Methylazoxymethanol by Alcohol Dehydrogenase1

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Production of a Highly Reactive Alkylating Agent from the Organospecific Carcinogen Methylazoxymethanol by Alcohol Dehydrogenase1 [CANCER RESEARCH 40, 4446-4450. December 1980] 0008-5472/80/0040-OOOOS02.00 Production of a Highly Reactive Alkylating Agent from the Organospecific Carcinogen Methylazoxymethanol by Alcohol Dehydrogenase1 Aaron Feinberg and Morris S. Zedeck Memorial Sloan-Kettering Cancer Center. New York, New York 10021 ABSTRACT tabolized by ADH to MAMAL (Chart 1) which could then act as a bifunctional alkylating agent. Grab and Zedeck (2) have The carcinogen methylazoxymethanol acetate induces a high shown that MAM is a substrate for the enzyme horse liver ADH. incidence of tumors in select tissues of the rat. It has been Moreover, they found that the 169,000 x g supernatant frac shown that methylazoxymethanol is a substrate for the enzyme tions from those tissues which are sensitive to the effects of horse liver alcohol dehydrogenase, and it has been suggested MAM could, unlike those tissues resistant to the carcinogen, that the organotropic effects are related to the metabolism of also utilize MAM as a substrate in NAD*- or NADP*-dependent methylazoxymethanol within the sensitive tissues by /S-nicotin- amide adenine dinucleotide (NAD*)- or /S-nicotinamide adenine reactions. Pyrazole, an inhibitor of ADH (1), inhibited the toxic (2) and carcinogenic (11 ) effects of MAM, giving support to the dinucleotide phosphate-dependent dehydrogenase reactions. role of this enzyme in the biological effects of this carcinogen. The fate of the product of the enzyme reaction, presumably Zedeck ef al. (7) reported that disulfiram, an inhibitor of alde the aldehydic form of methylazoxymethanol, and its mechanism hyde dehydrogenase, potentiates the biological effects of of reaction with cellular macromolecules have heretofore not MAM. Thus, it appears that MAMAL is the activated form of been investigated. We designed an assay to monitor the for mation of carbonium ions using sodium-["'C]acetate as the MAM. It was now of interest to determine whether the product of the enzyme reaction, presumably MAMAL, can also act as trapping agent. This nucleophile was added to an incubation mixture containing methylazoxymethanol, NAD*, and alcohol an alkylating agent and, if so, to compare its rate of reactivity with the parent compound. dehydrogenase. The amount of methylazoxymethanol con verted was determined by measuring the amount of reduced yS-nicotinamide adenine dinucleotide formed. Significantly more MATERIALS AND METHODS methyl [14C]acetate formed when methylazoxymethanol was Chemicals. Quaternary aminoethyl-Sephadex A25 was pur incubated with enzyme and NAD* as compared to when it .was chased from Pharmacia Fine Chemicals, Piscataway, N. J.; incubated alone. Analysis of the data comparing the amounts sodium [14C]acetate (56.5 Ci/mmol) was from New England of reduced /S-nicotinamide adenine dinucleotide and of Nuclear, Boston, Mass.; BSA, horse liver ADH, and NAD* were methyl[14C]acetate formed indicates that the aldehydic form of from Sigma Chemical Co., St. Louis, Mo.; pyrazole was from methylazoxymethanol is a very unstable compound which rap Eastman Chemicals, Rochester, N. Y.; and MAM acetate was idly releases carbonium ions. Experiments with A/-methyl-N- from Schwarz/Mann, Orangeburg, N. Y. Free MAM was pre nitrosourea, a methylating agent not requiring metabolic acti vation, showed no increase in the amount of methyl ['"C]acetate pared as described by Grab and Zedeck (2) and stored frozen in small aliquots. obtained when enzyme and NAD* were added as opposed to Resin Preparation and Sodium [14C]Acetate Purification. when enzyme was omitted. The significance of these findings Fifty g of quaternary aminoethyl-Sephadex A25, a strong anión is discussed in relation to the organotropism exhibited by exchanger, were converted to a resin having low selectivity by methylazoxymethanol. washing it 6 times with 500 ml of 1 M sodium acetate to exchange the chloride counterion to acetate. The resin was INTRODUCTION stirred gently for 15 to 30 min during each washing and finally washed extensively with water to remove the salts. MAM2 acetate is a potent carcinogen that induces acute and The sodium [14C]acetate was purified by loading approxi chronic effects in a few tissues of the rat, mainly duodenum, mately 20 juCi through a Chromaflex column (Kontes, Vineland, colon, liver, and kidney (3, 8-10). Since the alkylating moiety N. J.) filled with quaternary aminoethyl-Sephadex A25 resin derived from MAM (Chart 1) can occur spontaneously (4), it (0.6 x 3.0 cm). The resin was washed with water, and the was unclear why only a few tissues are affected by this carcin eluant was collected until no more radioactivity could be de ogen. The selectivity exhibited by other carcinogens in different tected. The resin was next eluted with 1 M sodium acetate. species, organs, and sexes is believed to be due, in part, to Fractions of 0.2 ml were collected and assayed for radioactiv metabolism of the carcinogen by the tissue sensitive to its ity. The peak of radioactivity was collected and diluted with effects. Schoental (5) had postulated that MAM might be me- glass-distilled water to give a specific activity of 0.74 ¡uCi/5 jiimol/20 n\. Alkylation Studies. All of the incubations were done at 37° 1 Supported by USPHS Grants CA 08748 from the National Cancer Institute and CA 15637 from the National Cancer Institute through the National Large in a total volume of 1 ml for 2 hr at pH 9.0 using 250 HIM Bowel Cancer Project and by the Elsa U. Pardee Foundation. 2 The abbreviations used are: MAM, methylazoxymethanol; ADH. alcohol glycine buffer or at pH 7.0 using 250 mM phosphate buffer. dehydrogenase; MAMAL. methylazoxymethanal; MNU, /V-nitroso-W-methylurea. The incubation vessels were capped, covered with parafilm, BSA, bovine serum albumin. and immersed in a 37°water bath up to the level of liquid in Received March 14. 1980; accepted September 10. 1980. the vessel. Rubber tubing was wrapped around the vessel 4446 CANCER RESEARCH VOL. 40 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1980 American Association for Cancer Research. Conversion of MAM by ADH MAM O ..O -R-NH2 CH '.-N-C-H»H,0 CH3 -N: N-CH2 OH Sto* Non-enzymotic Fas, HO HCOH +CH3-N=N-OH HCOOH*CHj -N'N-OH R-N-C-H » CH,-N = N-OH CHj* CH,' »N, Chart 1. Pathways illustrating MAM decomposition, proposed metabolism, and subsequent interactions. R—WH2represents either DNA, RNA, or protein. above the level of liquid, and cold water was circulated through the tubing to condense any vapors. For experiments at pH 9.0 and at pH 7.0, the amounts of NAD+, pyrazole, MNU, BSA, and sodium [14C]acetate were 50 /imol, 5 /¿mol,10jumol, 200 jug, and 0.74 ¡uCi,respectively. The amounts of ADH used for the experiments at pH 9.0 and pH 7.0 were 200 /¿gand1.6 mg, respectively. MAM was added to give varying concentrations. NAD+ and pyrazole were dis solved in glass-distilled water, BSA, or ADH in 0.1 M phosphate buffer, pH 7.5 (containing 0.015% BSA to stabilize the en zyme), and MNU was added in 50 /il dried distilled acetone. NAD+, ADH, and MNU solutions were prepared daily, and' replicate experiments were performed on different days. After the 2-hr incubation period, the tube was cooled in ice for 10 min. The sample was then loaded onto a 1.6-cm-diam- eter column containing 8 to 8.5 ml of swollen QAE Sephadex- A25 resin and eluted with 20 ml of distilled water to collect the 10 15 20 25 30 35 40 45 unadsorbed methyl [14C]acetate. This was followed by 1 M sodium formate to elute the bound [14C]acetate. Sodium for Fraction Chart 2. Formation of methyl ['"CJacetate and its separation from sodium mate was chosen because, unlike other salts, it allowed the ["C]acetate. Sodium [MC]acetate (O), sodium ('"CJacetate and MAM (A), or sodium [MC]acetate with MAM and ADH (•)was incubated, and the mixtures formation of one phase when mixed with the Hydrofluor scin were analyzed as described under "Materials and Methods"; the total cpm eluted tillation fluid. The flow rate was 0.2 to 0.3 ml/min, and fractions in Fractions 34 to 39 were 1,292,303 (O); 1,255,093 (A); and 1,262,256 (•). of 1.4 to 1.6 ml were collected and then transferred by pipet Arrows, time when either H2O or 1 M sodium formate was used as eluant. into scintillation vials. Each collection tube was rinsed with two 200-^1 portions of water which were also added to the vials. Identification of Alkylated Product. A 4-ml reaction mixture The fractions were mixed with 18 ml Hydrofluor, and the containing NAD* and enzyme in concentrations described radioactivity was measured; the counting efficiency was 80%. above with 17.2 rriM MAM was incubated for 2 hr at 37°.The To determine the molarity of the free MAM following its mixture was extracted 6 times with 4-ml portions of cyclohex- preparation from MAM acetate, an aliquot of the solution was ane. To the combined fractions were added 25 ml of distilled diluted with 5 ml water to give a concentration of 1 A2i5/ml. methyl acetate, and the mixture was distilled. The distillate was MAM acetate, unlike free MAM, is readily extractable from collected in 5-ml portions directly into counting vials kept cool water by ether. This solution was then extracted 15 times with with dry ice, and the radioactivity of each fraction was deter 5 ml of ether saturated with water to extract any remaining mined. MAM acetate, and the A2is of the water layer containing the free MAM was measured after each 3 extractions.
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