Myristicin and Elemicin: Potentially Toxic Alkenylbenzenes in Food

Abstract

Alkenylbenzenes represent a group of naturally occurring substances that are synthesized as secondary metabolites in various plants, including nutmeg and basil. Many of the alkenylbenzene-containing plants are common spice plants and preparations thereof are used for flavoring purposes. However, many alkenylbenzenes are known toxicants. For example, safrole and methyleugenol were classified as genotoxic carcinogens based on extensive toxicological evidence. In contrast, reliable toxicological data, in particular regarding genotoxicity, carcinogenicity, and reproductive toxicity is missing for several other structurally closely related alkenylbenzenes, such as myristicin and elemicin. Moreover, existing data on the occurrence of these substances in various foods suffer from several limitations. Together, the existing data gaps regarding exposure and toxicity cause difficulty in evaluating health risks for humans. This review gives an overview on available occurrence data of myristicin, elemicin, and other selected alkenylbenzenes in certain foods. Moreover, the current knowledge on the toxicity of myristicin and elemicin in comparison to their structurally related and well-characterized derivatives safrole and methyleugenol, especially with respect to their genotoxic and carcinogenic potential, is discussed. Finally, this article focuses on existing data gaps regarding exposure and toxicity currently impeding the evaluation of adverse health effects potentially caused by myristicin and elemicin.

Keywords: alkenylbenzenes; elemicin; flavoring; methyleugenol; myristicin; safrole.

Figure 1

Structural formulas of methyleugenol, elemicin, safrole, and myristicin.

Figure 2

Metabolite excretion of safrole in the rat is reported to be 93% within 72 h, and most of this material (86%; [79]) would consist of metabolites formed via demethylenation of the methylenedioxy moiety to yield carbon monoxide or formate and the dihydroxy-benzene moiety [80]. The other metabolic routes observed were allylic hydroxylation and the epoxide-diol pathway [70,79]. Oxidations of the allylic side chain of safrole may proceed (i) via an epoxide resulting in side chain propane diols during different stages of the metabolic steps [72], or (ii) via 1′-hydroxylation followed by sulfonation that might lead to a reactive carbocation intermediate [5]. Other possible steps of metabolic ways of safrole are (iii) the subsequent oxidation of the 1′-hydroxysafrole to the 1′-oxo-safrole [81], (iv) oxidation at the 3′-position to yield 3′-hydroxy-isosafrole, and (v) the demethylenation of safrole to 4-allylcatechol that may isomerize to its quinone-methide [82,83,84]. The occurrence of glutathione conjugates at the 1′-position may be indicative of the intermediate formation of para-quinone methide tautomers [82], whereas glutathione conjugates at the benzene ring point to reactions with ortho-quinone intermediates [82]. CYP: cytochrome P450 monooxygenases; SULT: sulfotransferases; EH: epoxide hydrolases; nuc: nucleophilic structures such as DNA or proteins.