This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Phillips, D. H. Articles by Adams, B. Search for Related Content PubMed PubMed Citation Articles by Phillips, D. H. Articles by Adams, B.

N² Atom of Guanine and N⁶ Atom of Adenine Residues as Sites for Covalent Binding of Metabolically Activated 1'-Hydroxysafrole to Mouse Liver DNA in Vivo¹

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

Administration of 1'-[2',3'-³H]hydroxysafrole to adult female mice resulted in the formation of DNA-, ribosomal RNA-, and protein-bound adducts in the liver that reached maximum levels within 24 hr. The levels of all three macromolecule-bound adducts decreased rapidly between 1 and 3 days after injection, at which time the amounts of the DNA-bound adducts essentially plateaued at approximately 15% of the maximum level. The amounts of the protein and ribosomal RNA adducts were very low by 20 days.

Comparison by high-performance liquid chromatography of the deoxyribonucleoside adducts obtained from the hepatic DNA with those formed by reaction of deoxyguanosine and deoxyadenosine with 1'-acetoxysafrole, 1'-hydroxysafrole-2',3'-oxide, and 1'-oxosafrole indicated that the four in vivo adducts studied were derived from an ester of 1'-hydroxysafrole. Three of the four in vivo adducts comigrated with adducts formed by reaction of 1'-acetoxysafrole with deoxyguanosine; the fourth adduct comigrated with the major product of the reaction of this ester with deoxyadenosine. Adduct formation in vivo at low levels by the other two electrophilic metabolites was not excluded. The three adducts obtained by reaction of 1'-acetoxysafrole with deoxyguanosine appeared to be substituted on the 2-amino group of the guanine residue on the basis of their partitions between aqueous buffer solutions and 1-butanol:ethyl ether as a function of pH and their retention of ³H from [8-³H]deoxyguanosine. The corresponding three adducts derived from the hepatic DNA of mice given 1'-[2',3'-³H]hydroxysafrole had pH partition patterns not significantly different from the three adducts formed in vitro. Adduct II was further characterized from its nuclear magnetic resonance spectrum as N²-(trans-isosafrol-3'-yl)deoxyguanosine. Adduct IV, derived from the reaction of 1'-acetoxysafrole with deoxyadenosine 5'-phosphate, was characterized in the same manner as N⁶-(trans-isosafrol-3'-yl)deoxyadenosine.

¹ This work was supported by Grants CA-07175 and CA-22484 from the National Cancer Institute, USPHS.

² Present address: Department of Biological Sciences, Stanford University, Stanford, Calif. 94305.

³ To whom requests for reprints should be addressed.

Received 12/ 5/80. Accepted 4/ 1/81.

This article has been cited by other articles:

				C.-J. Liu, C.-L. Chen, K.-W. Chang, C.-H. Chu, and T.-Y. Liu Safrole in betel quid may be a risk factor for hepatocellular carcinoma: case report Can. Med. Assoc. J., February 1, 2000; 162(3): 359 - 360. [Full Text] [PDF]

				C.-L. Chen, C.-W. Chi, K.-W. Chang, and T.-Y. Liu Safrole-like DNA adducts in oral tissue from oral cancer patients with a betel quid chewing history Carcinogenesis, December 1, 1999; 20(12): 2331 - 2334. [Abstract] [Full Text] [PDF]

				S.G. Kim, A. Liem, B.C. Stewart, and J.A. Miller New studies on trans-anethole oxide and trans-asarone oxide Carcinogenesis, July 1, 1999; 20(7): 1303 - 1307. [Abstract] [Full Text] [PDF]