Inhibition of Human CYP3A4, UGT1A6, and P-glycoprotein with Halogenated Xanthene Food Dyes and Prevention by Superoxide Dismutase

Abstract

Synthetic food dyes are xenobiotics, and, after ingestion, portions of these dyes may be absorbed and metabolized by phase I and II drug-metabolizing enzymes, and excreted by transporters of phase III enzymes. In the previous report, it was shown that inhibition of UDP-glucuronosyltrasnferase 1A6 occurred following ingestion of phloxine, erythrosine, and rose bengal present in 12 permitted synthetic food dyes. In this report, the influence of dyes was examined on CYP3A4, a major phase I drug-metabolizing enzyme, and P-glycoprotein, a major transporter by synthetic food dyes. Human cytochrome P-450 (CYP) 3A4 and P-glycoprotein were inhibited by xanthene food dyes. The IC₅₀ values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the level of inhibition of UGT1A6 produced by three haloganated xanthene food dyes in the previous report, except acid red, which inhibited only CYP3A4. Data suggest that inhibition by dyes is not enzyme specific but may be in a membrane-specific or protein-specific manner, such as conformational changes in protein. In the previous study, it was suggested that inhibition by dyes depended upon light irradiation due to generation of ¹O₂ from these dyes. In this study, the influence of superoxide dismutase and catalase on inhibition by dyes was examined. Superoxide dismutase but not catalase was effective in preventing the inhibition of UGT1A6 by the dyes. Data suggest that superoxide anions, originating from dyes via light irradiation, may attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins in skin and may lead to skin damage.