1'-Hydroxy-2',3'-dehydroestragole is a synthetic acetylenic analogue of
1'-hydroxyestragole, the proximate carcinogenic metabolite of the naturally occurring hepatocarcinogen
estragole (1-allyl-4-methoxybenzene). This analogue is considerably more potent than
1'-hydroxyestragole as an hepatocarcinogen in mice. 1'-Acetoxy-2',3'-dehydroestragole reacted readily with
deoxyguanosine or
deoxyguanosine 5'-monophosphate at neutrality to form two adducts. Adduct I, isolated and characterized after dephosphorylation of the
deoxyguanosine 5'-monophosphate product, was a 1:1 mixture of two diastereomers of N2-(2',3'-dehydroestragol-1'-yl)deoxyguanosine. Adduct II was shown to be N-7-(2',3'-dehydroestragol-1'-yl)guanine. The reaction of
deoxyadenosine with 1'-acetoxy-2',3'-dehydroestragole at neutrality produced Adducts III and IV. Adduct IV was characterized as N6-(2',3'-dehydroestragol-1'-yl)deoxyadenosine. Administration of [1'-3H]-1'-hydroxy-2',3'-dehydroestragole to male preweanling C57BL/6J x C3H/HeJ F1 (hereafter called B6C3F1) mice resulted in extensive covalent binding to hepatic
DNA,
RNA, and
protein. On hydrolysis of the
DNA to
nucleosides, a single major adduct accounted for greater than 85% of the
DNA-bound 3H. This adduct comigrated with Adduct I in two high performance liquid chromatography systems, had a pH partition profile identical to that of Adduct I, and was present as a mixture of diastereomers in a ratio of 2:1. The identity of the
DNA adduct formed in vivo with Adduct I from the reaction of 1'-acetoxydehydroestragole indicated that a reactive
ester was a major metabolic precursor in vivo. There was no significant loss of Adduct I from the hepatic
DNA by 21 days after a single injection of a carcinogenic dose of
1'-hydroxy-2',3'-dehydroestragole. Adducts II, III, and IV were not detected in significant amounts in the hepatic
DNA isolated by a
phenol extraction method or by a more rapid
hydroxylapatite method. Cytosolic
sulfotransferase activity was demonstrated for 1-hydroxy-2',3'-dehydroestragole in mouse liver, and inhibition of this activity by greater than 95% was found on addition of 10 microM
pentachlorophenol. The administration of
pentachlorophenol (0.04 mumol/g
body weight) 45 min prior to a single dose of
1'-hydroxy-2',3'-dehydroestragole (0.04 mumol/g
body weight) in 12-day-old male B6C3F1 mice greatly inhibited (87-97%) the covalent binding of
1'-hydroxy-2',3'-dehydroestragole to hepatic macromolecules and the formation of
hepatomas at 10 months.(ABSTRACT TRUNCATED AT 400 WORDS)