DNA adducts from alkoxyallylbenzene herb and spice constituents in cultured human (HepG2) cells

Abstract

Alkoxy derivatives of allylbenzene, including safrole, estragole, methyleugenol, myristicin, dill apiol, and parsley apiol, are important herb and spice constituents. Human exposure occurs mainly through consumption of food and drinks. Safrole, estragole, and methyleugenol are weak animal carcinogens. Experimental data reveal the genotoxicity and/or carcinogenicity of some allylbenzenes; however, except for safrole, the potential capacity of allylbenzenes for forming adducts in human cellular DNA has not been investigated. In the present study, we have exposed metabolically competent human hepatoma (HepG2) cells to three concentrations (50, 150, and 450 muM) of each of the six aforementioned allylbenzenes and shown by the monophosphate (32)P-postlabeling assay that each compound formed DNA adducts. With the exception of methyleugenol, DNA adduction was dose dependent, decreasing in the order, estragole > methyleugenol > safrole approximately myristicin > dill apiol > parsley apiol. These results demonstrate that safrole, estragole, methyleugenol, myristicin, dill apiol, and parsley apiol are capable of altering the DNA in these cells and thus may contribute to human carcinogenesis.

Physiologically based kinetic modeling of the bioactivation of myristicin

“…In agreement with hepatocarcinogenicity in mice (Miller et al 1983), DNA adduct formation upon exposure to myristicin was generally lower and less persistent than DNA adduct formation upon exposure to methyleugenol and estragole and appeared to be about twofold lower than DNA adduct formation upon exposure to safrole, both in in vitro study (Zhou et al 2007a) and in in vivo studies (Table 1) (Phillips et al 1984; Randerath et al 1984). N 2 -(trans-isomyristicin-3′-yl)-2′-deoxyguanosine was found to be the major myristicin DNA adduct formed when mice were given cola drinks instead of water up to 8 weeks.…”

“…The data supporting a genotoxic mode of action for the tumor induction by the alkenylbenzenes rather come from studies reporting DNA adduct formation. In these studies, myristicin, as well as estragole, methyleugenol, and safrole, all showed positive results (Zhou et al 2007a; Kobets et al 2016; Phillips et al 1984; Randerath et al 1984). A schematic overview of the detoxification and bioactivation of myristicin that is similar to that of its structurally related compound safrole (Swanson et al 1979; Borchert et al 1973; Drinkwater et al 1976) is shown in Fig.…”

An antibacterial and antifungal phenylpropanoid from Carum montanum (Coss. et Dur.) Benth. et Hook.

“…Apiole (3) was less studied, but nevertheless showed also a wealth of biological activities, such as antifungal (Meepagala et al, 2005;Razzaghi-Abyaneh et al, 2007), antioxidant (Zhang et al, 2006), phytotoxic (Meepagala et al, 2005) and an even more potent synergistic insecticide potential than 2 (Lichtenstein et al, 1974). In fact, in most of the studies where 2 and 3 or 4 were compared regarding their biological activities, 3 and 4 were more potent than 2 (Lichtenstein et al, 1974;Zhang et al, 2006;RazzaghiAbyaneh et al, 2007), while unwanted carcinogenic and genotoxic properties (well established for safrole and estragole) decreased with further methoxylations of the aromatic nucleus in the order: safrole > 2 > 3 > 4 (Zhou et al, 2007). Only one study recently explored the biological activity of a nothoapiole containing mixture through the evaluation of the antioxidant, antibacterial and antifungal properties of Carum nigrum essential oil and oleoresin (Singh et al, 2006), but this substance was contained in low percentage in these mixtures and was not evaluated alone.…”

Joint FAO/WHO Expert Committee on Food Additives (JECFA)

“…Also, the ratio of major/minor DNA adducts was highest for methyl eugenol in both HepG2 cells and mouse liver and lowest for estragole and safrole. The authors suggest that decreased steric hindrance is related to increased formation of the minor N 2 -(allylbenzene-1 -yl) adduct (Zhou et al, 2007).…”