• Rietjens IM, Cohen SM, Fukushima S, Gooderham NJ, Hecht SS, Marnett LJ, Smith B, Adams T, Bastaki M, Harman C, Taylor S. The impact of structural and metabolic variation on the toxicity and carcinogenicity of hydroxy- and alkoxy- substituted allyl- and propenylbenzenes. Chemical research in toxicology. 2014 May 23. PMID: 24857813 [PubMed].


The metabolic fate of a compound is determined by numerous factors including its chemical structure. Although the metabolic options for a variety of functional groups are well understood, and can often provide a rationale for comparison of toxicity based on structural analogy, at times, quite minor structural variations may have major consequences for metabolic outcomes and toxicity. In this paper, the effects of structural variations on metabolic outcomes is detailed for a group of related hydroxy- and alkoxy- substituted allyl- and propenylbenzenes. These classes of compounds are naturally occurring constituents of a variety of botanical based food items. The classes vary from one another by the presence or absence of alkylation of their para-hydroxyl substituents and/or the position of the double bond in the alkyl side chain. We provide an overview of how these subtle structural variations alter the metabolism of these important food-borne compounds, ultimately influencing their toxicity, particularly their DNA reactivity and carcinogenic potential. The data reveal that detailed knowledge of the consequences of subtle structural variations for metabolism is essential for adequate comparison of structurally related chemicals. Taken together, it is concluded that predictions in toxicological risk assessment should not be performed on the basis of structural analogy only, but should include analogy of metabolic pathways across compounds and species.