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

✍ Scribed by Phillips, David H. ;Hanawalt, Philip C. ;Miller, James A. ;Miller, Elizabeth C.

• Publisher: Wiley (John Wiley & Sons)
• Year: 1981
• Tongue: English
• Weight: 453 KB
• Volume: 16
• Category: Article
• ISSN: 0275-3723
• DOI: 10.1002/jsscb.1981.380160108

✦ Synopsis

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′‐^3^H]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 N^2^‐(trans‐isosafrol‐3′‐Y1)‐deoxyguanosine, and the deoxyadenosine adduct has been similarly characterized as N^6^‐(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.