Structure-Activity Studies of the Hepatocarcinogenicities of Alkenylbenzene Derivatives Related to Estragole and Safrole on Administration to Preweanling Male C57BL/6J × C3H/HeJ F₁ Mice¹

Further information on the structure-activity relationships among the synthetic and naturally occurring alkenylbenzene derivatives was obtained by examining their hepatocarcinogenicities for mice following administration of one or a few doses prior to weaning. Under these conditions preweanling male C3H/HeJ mice were more susceptible than male C57BL/6J mice or females of either strain to liver tumor induction by 1′-hydroxyestragole (1′-hydroxy-1-allyl-4-methoxybenzene) and 1′-hydroxyestragole (1′-hydroxy-1-allyl-3,4-methylenedioxybenzene). Male C57BL/6J × C3H/HeJ F₁ mice given a single dose of 1′-hydroxyestragole at 12 days of age developed approximately twice as many hepatomas per liver as did those given the same dose per g of body weight at 1 day of age. The acetylenic compounds 1′-hydroxy-2′,3′-dehydroestragole and 1′-hydroxy-2′,3′-dehydroestragole were the most potent derivatives studied; they were 5- and 10-fold more potent (based on the average numbers of hepatomas per liver) than the corresponding allylic benzene derivatives. 1′-Acetoxyestragole and 1′-acetoxysafrole had activities similar to those of their respective 1′-hydroxy derivatives; estragole derivatives were consistently 2- to 3-fold more potent than the related safrole derivatives. 1′-Hydroxyelemicin (1′-hydroxy-1-allyl-3,4,5-trimethoxybenzene), its acetic acid ester 1′-oxoestragole, and 3′-bromo-trans-anethole (3′-bromo-1-trans-propenyl-4-methoxybenzene) each had very weak, but statistically significant, hepatocarcinogenic activity. The propenylic derivatives cis-anethole, trans-isosafrole, 1:1 cis, trans-isosafrole, 3′-hydroxy-trans-anethole, piperine, and trans-cinnamaldehyde showed no hepatocarcinogenic activity at the levels examined. In contrast, the propenylic derivatives cis- and trans-asarone (1-propenyl-2,4,5-trimethoxybenzene) were each active; the hepatocarcinogenicities of the asarones were not inhibited by prior administration of pentachlorophenol, a sulfotransferase inhibitor that abolished the hepatocarcinogenicity of estragole under the same conditions. Furthermore, precocene II (6,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran), a cyclic propenylic plant metabolite and asarone analogue, showed strong hepatocarcinogenic activity similar to that of 1′-hydroxy-2′,3′-dehydroestragole and 1′-hydroxy-2′,3′-dehydrosafrole; precocene I (the 7-methoxy analogue of precocene II) was less active than precocene II but more active than cis-asarone.