The in vivo formation and repair of DNA adducts from 1′‐hydroxysafrole

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Abstract
1′-Hydroxysafrole is a proximate carcinogenic metabolite of the naturally occurring hepatocarcinogen safrole. Comparison by high-performance liquid chromatography of the nucleoside adducts obtained from hepatic DNA of adult female mice treated with [2′,3′-3H]1′-hydroxysafrolc with those formed by reaction of deoxyribonucleo-sides with electrophilic derivatives of 1′-hydroxysafrole indicated that the four in vivo adducts studied were derived from an ester of 1′-hydroxysafrole. Three of the four adducts comigrated with products of the reaction of 1′-acetoxysafrole with deoxyguanosine, whereas the fourth adduct comigrated with the major reaction product of the ester with deoxyadenosine. Analysis of the three deoxyguanosine ad-ducts indicated that all three involve substitution on the 2-amino group of guanine. A sample of the major adduct prepared from deoxyguanylic acid has been charac-terized from its NMR spectrum as N2-(trans-isosafrol-3′-Y1)-deoxyguanosine, and the deoxyadenosine adduct has been similarly characterized as N6-(trans-isosafrol-3′-yl)-deoxyadenosine. Repair replication was measured in cultured human T98G cells exposed to 1′-acetoxysafrole using the combined 5-bromodcoxyuridine density label and radioiso-topic label metnod. At a concentration of 1 mM 1′-acetoxysafrole, the amount of repair synthesis approached maximum values only about 15% of those obtained af-ter saturating doses of ultraviolet light. Repair patch size distribution was found to be similar in cells treated with ultraviolet light or 1′-acetoxysafrole as determined by the density of repair-labeled DNA relative to that of parental DNA.

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