Structure-activity studies of the hepatocarcinogenicities of alkenylbenzene derivatives related to estragole and safrole on administration to preweanling male C57BL/6J × C3H/HeJ F 1 mice

Abstract

Abstract 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 F 1 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-2 H -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.