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N2 Atom of Guanine and N6 Atom of Adenine Residues As Sites for Covalent Binding of Metabolically Activated 1'-Hydroxysafrole to Mouse Liver DMA in V/Vo1

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N2 Atom of Guanine and N6 Atom of Adenine Residues As Sites for Covalent Binding of Metabolically Activated 1'-Hydroxysafrole to Mouse Liver DMA in V/Vo1 [CANCER RESEARCH 41, 2664-2671, July 1981] 0008-5472/81 /0041-OOOOS02.00 N2 Atom of Guanine and N6 Atom of Adenine Residues as Sites for Covalent Binding of Metabolically Activated 1'-Hydroxysafrole to Mouse Liver DMA in V/vo1 David H. Phillips,2 James A. Miller,3 Elizabeth C. Miller, and Bruce Adams McArdle Laboratory for Cancer Research [D. H. P., J. A. M., E. C. M.¡and Department of Chemistry ¡B.A.], University of Wisconsin, Madison. Wisconsin 53706 ABSTRACT use of safrole and sassafras oil (containing safrole) as food Administration of 1'-[2',3'-3H]hydroxysafrole to adult female additives was banned in the United States in 1960, safrole continues to be ingested in small amounts by humans since it mice resulted in the formation of DMA-, ribosomal RNA-, and is a minor component of a number of other essential oils and of protein-bound adducts in the liver that reached maximum levels some herbs and spices, including anise, basil, nutmeg, mace, within 24 hr. The levels of all three macromolecule-bound and pepper (12, 13, 20). adducts decreased rapidly between 1 and 3 days after injec Current evidence (reviewed in Refs. 22 and 27) suggests tion, at which time the amounts of the DMA-bound adducts that a property common to most chemical carcinogens is that essentially plateaued at approximately 15% of the maximum their biologically active forms are electrophilic. The majority of level. The amounts of the protein and ribosomal RNA adducts carcinogens are not electrophilic as such and must undergo were very low by 20 days. metabolic activation in vivo to reactive species of this type. Comparison by high-performance liquid chromatography of Studies on safrole (6, 7, 24, 28-30, 34, 35) indicated the the deoxyribonucleoside adducts obtained from the hepatic metabolic formation of several electrophilic metabolites. Borch- DMA with those formed by reaction of deoxyguanosine and ert ef al. (5, 6) showed that 1'-hydroxysafrole is a major deoxyadenosine with 1'-acetoxysafrole, 1'-hydroxysafrole- 2',3'-oxide, and 1'-oxosafrole indicated that the four in vivo metabolite of safrole in the rat and mouse and that it possesses greater carcinogenic activity than does the parent compound adducts studied were derived from an ester of 1'-hydroxysaf- in these species. 1'-Hydroxysafrole undergoes further metab role. Three of the four in vivo adducts comigrated with adducts olism by rat and mouse liver preparations to 1'-sulfonoxysafrole formed by reaction of 1'-acetoxysafrole with deoxyguanosine; and 1'-hydroxysafrole-2',3'-oxide (30, 34) (Chart 1). Both the the fourth adduct comigrated with the major product of the latter metabolite and a model analog of the former, 1'-acetox reaction of this ester with deoxyadenosine. Adduct formation ysafrole, possess electrophilic, carcinogenic, and mutagenic in vivo at low levels by the other two electrophilic metabolites activity (5, 6, 29, 34, 35). In addition, 1'-oxosafrole, small was not excluded. The three adducts obtained by reaction of amounts of which are found as Mannich base derivatives in the 1'-acetoxysafrole with deoxyguanosine appeared to be substi urine of rats administered safrole (24), exhibits electrophilic tuted on the 2-amino group of the guanine residue on the basis activity (34). However, 1'-oxosafrole has not shown mutagenic of their partitions between aqueous buffer solutions and 1- or carcinogenic activity (34, 35). We have reported recently butanohethyl ether as a function of pH and their retention of 3H (26) that 1'-hydroxyestragole, a compound structurally related from [8-3H]deoxyguanosine. The corresponding three adducts to 1'-hydroxysafrole and a proximate carcinogenic metabolite derived from the hepatic DNA of mice given 1'-[2',3'-3H]hy- of the natural flavoring agent estragóle (1-allyl-4-methoxyben- droxysafrole had pH partition patterns not significantly different zene) (9), is metabolically activated in mouse liver in vivo to a from the three adducts formed in vitro. Adduct II was further derivative, presumably a 1'-ester, that reacts covalently with characterized from its nuclear magnetic resonance spectrum the exocyclic amino groups of guanine and adenine residues as /V2-(frans-isosafrol-3'-yl)deoxyguanosine. Adduct IV, de in DNA. The present paper reports that the DNA adducts rived from the reaction of 1'-acetoxysafrole with deoxyadeno formed in mouse liver after administration of 1'-hydroxysafrole sine 5'-phosphate, was characterized in the same manner as are analogous to the 1'-hydroxyestragole:DNA adducts (26), iVXfrans-isosafrol-S'-yOdeoxyadenosine. and evidence for their structures is presented. The earlier assignment of the structure of the major product of the reaction INTRODUCTION of 1'-acetoxysafrole with GMP as O6-(isosafrol-3'-yl)guanylic acid (6, 34) was found to be incorrect. Safrole [1 -allyl-3,4(methylenedioxy)benzene], a naturally oc curring flavoring agent that is the major constituent of oil of MATERIALS AND METHODS sassafras (12, 13, 20), possesses weak hepatocarcinogenic activity when fed to adult rats or mice (1, 5, 14, 15, 21) and Safrole Derivatives. The syntheses of 1'-hydroxysafrole and moderate hepatocarcinogenic activity when injected into mice 1'-acetoxysafrole (6) and of 1'-oxosafrole, 1'-hydroxysafrole- during the first few weeks after birth (5, 11, 35). Although the 2',3'-oxide, 1'-hydroxy-2',3'-dehydrosafrole, and 1'-{2',3'- 3H]hydroxysafrole (34) have been described previously. ' This work was supported by Grants CA-07175 and CA-22484 from the National Cancer Institute. USPHS. Hepatic DNA, rRNA, and Protein from Mice Treated with 2 Present address: Department of Biological Sciences, Stanford University. 1'-{3H]Hydroxysafrole. Female CD-1 mice (Charles River Stanford, Calif. 94305. 3 To whom requests for reprints should be addressed. Breeding Laboratory, Wilmington, Mass.), 8 to 10 weeks old (mean weight, 30 g) were given i.p. injections of 1'-[2',3'- Received December 5. 1980; accepted April 1, 1981. 2664 CANCER RESEARCH VOL. 41 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1981 American Association for Cancer Research. 1'-Hydroxysafrole-DNA Adducts in Mouse Liver 1-ÇH- incubated with 4 units of alkaline phosphatase (Sigma) at 37° for 48 hr. The nucleosides which precipitated were washed with water and dried in a vacuum. HPLC analysis revealed that H-C-CH =CH2 the material (18 mg) obtained from Fractions 51 to 55 from the OH I-HYDROXYSAFROLE dGMP reaction consisted of a single product. Earlier fractions contained a mixture of this product and unreacted dGuo, and later fractions contained 2 minor products in addition to the major product found in Fractions 51 to 55. Similarly, the material (28 mg) from Fractions 61 to 70 of the dAMP reaction -,-CH i—CHo -CH, mixture contained a single product; earlier fractions contained additional unreacted dAdo, and subsequent fractions con tained additional adducts. C-CH=CH2 H-Ç-CH=CH2 H-Ç-CH-CH2 NMR spectra were determined on solutions of the adducts in 0 0-S03H OH M dimethyl sulfoxide-d6 (5 mg in 0.4 ml) by use of a 270-MHz I'-OXO- I'-SULFONOXY- I-HYDROXY Bruker WH 270 spectrometer equipped with a B-NC 12 Nicolet SAFROLE SAFROLE SAFROLE- 2',y- OXIDE computer. Chart 1. Pathways of metabolism of 1'-hydroxysafrole, a proximate carcino HPLC Chromatography. Chromatography of DNA hydroly genic metabolite of safrole, to electrophilic species. sates and marker nucleoside adducts was performed on an ALC/GPC 294 liquid Chromatograph (Waters Associates, Mil- 3H]hydroxysafrole (404 mCi/mmol, 12 jumol/mouse in 0.1 ml ford, Mass.) equipped with a Model U6K injector, a Model 660 trioctanoin). At the times indicated, the animals were killed by solvent programmer, a Model 440 absorbance detector, an cervical dislocation, and the livers from groups of 5 mice were Omniscribe B-5000 strip chart recorder (Houston Instruments, pooled for isolation of DMA, rRNA, and protein by the method Austin, Texas), and a Spherisorb ODS 5 /im reverse-phase of Irving and Veazey (16). DNA and rRNA were dissolved in column (Altex Scientific Inc., Berkeley, Calif.). The solvent Tris buffer (0.01 M, pH 7.0) and hydrolyzed enzymatically to systems used were: System A, 100% water for 5 min followed nucleosides by the method of Baird and Brookes (2). Protein by a linear (Program 6) gradient of 15 to 40% acetonitrile:water was dissolved in Soluene (Packard Instrument Co., Inc., Down for 35 min; System B, 25% acetonitrile:water; System C, 45% ers Grove, III.). Aliquots of digests of the 3 macromolecules methanol:water. For each system, the flow rate used was 2 ml/ were added to Aquassure scintillation fluid (New England Nu min. As noted previously (26), the retention times of adducts clear, Boston, Mass.) and assayed for radioactivity in Isocap/ may be altered by 1 to 2 min depending on the quantity of 300 (Nuclear Chicago, Inc., Chicago, III.) or Mark Ml/6880 other materials, such as unmodified nucleosides, necessarily (Searle Analytic, Inc., Des Plaines, III.) scintillation spectrome coinjected with them. Thus, the retention times quoted for ters. External standardization was used to convert all of the adducts are not absolute, and it was essential for determining data to dpm. the identical natures of in vivo- and in wfro-derived adducts Preparation of Nucleoside Adducts. 14C-Labeled nucleo- that they be eluted simultaneously after coinjection on HPLC. side adduct markers were prepared by reacting the appropriate pH Partition Coefficient Patterns of Adducts. Aliquots (50 1'-hydroxysafrole derivative (10 mg in 0.5 ml of ethanol) with to 100 ííl)ofthe adduct-containing fractions eluted from HPLC [14C]dGuo4 or [14C]dAdo (2 mg containing 0.5 jiCi in 0.5 ml columns were partitioned by the procedure of Moore and 0.01 M Tris, pH 7.0).
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