title: Use of the Combination Index to determine interactions between plant-derived phenolic acids on hepatotoxicity endpoints in human and rat hepatoma cells.
abstract: The beneficial or adverse effects of isolated phytochemicals are not always concordant with effects of the botanical dietary supplements from which they were derived. This disparity could be due to interactions between the various phytochemicals present in the whole plant. The phenolic acids, rosmarinic acid (RA), caffeic acid (CA) and ferulic acid (FA) are widely present in foods and dietary supplements, and they are assumed to exert various beneficial biological effects. However, there is little data on the potential biological interactions of these three phenolic acids which commonly occur together and are linked metabolically. In the present study, liver toxicity of the three phenolic acids was assessed on the three compounds singly and in various binary and one ternary combinations. A series of in vitro endpoints relevant to liver toxicity were evaluated in both a human (HepG2/C3A) and rat (MH1C1) hepatocyte cell line. The Combination Index (CI) was calculated for each endpoint from both the concentration responses of the single compounds and the responses of the various binary and ternary mixtures. Both synergistic and antagonistic interactions were observed for some endpoints and some combinations of test agents. Interactions were most prevalent in measures of oxidative stress and cytochrome P450 activities in both cell types. There was only a 53% concordance between the rat and human cells which may be suggestive of species differences. The data suggest an approach for better characterizing the beneficial or adverse effects of complex botanical products through evaluation of interactions between individual phytochemical components.
authors: Division of Toxicology, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD 20708, USA.
authors: Yitong
authors: Y
authors: Liu
authors: Thomas J
authors: TJ
authors: Flynn
authors: Martine S
authors: MS
authors: Ferguson
authors: Erica M
authors: EM
authors: Hoagland
mesh_terms: D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D002934:Cinnamates / Q000494:pharmacology*; D003373:Coumaric Acids / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000737:chemistry; D053630:Depsides / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000187:drug effects*; D018384:Oxidative Stress; D051381:Rats; D020112:Rhodamine 123 / Q000737:chemistry; D000097123:Rosmarinic Acid
chemical_list: D002109:Caffeic Acids; D002934:Cinnamates; D003373:Coumaric Acids; D019363:Cytochrome P-450 CYP1A1; D053630:Depsides; D020112:Rhodamine 123; D000097123:Rosmarinic Acid; C004999:ferulic acid; C040048:caffeic acid