Abstract
The synthetic food dyes studied were rose bengal (RB), phroxine (PL), amaranth, erythrosine B (ET), allura red, new coccine, acid red (AR), tartrazine, sunset yellow FCF, brilliant blue FCF, and indigo carmine. First, data confirmed that these dyes were not substrates for CYP2A6, UGT1A6, and UGT2B7. ET inhibited UGT1A6 (glucuronidation of p-nitrophenol) and UGT2B7 (glucuronidation of androsterone). We showed the inhibitory effect of xanthene dye on human UGT1A6 activity. Basic ET, PL, and RB in those food dyes strongly inhibited UGT1A6 activity, with IC50 values = 0.05, 0.04, and 0.015 mM, respectively. Meanwhile, AR of an acidic xanthene food dye showed no inhibition. Next, we studied the inhibition of CYP3A4 of a major phase I drug-metabolizing enzyme and P-glycoprotein of a major transporter by synthetic food dyes. Human CYP3A4 and P-glycoprotein were also inhibited by basic xanthene food dyes. The IC50 values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the inhibition level of UGT1A6 by three halogenated xanthene food dyes (ET, PL, and RB) described above, except AR, like the results with UGT1A6 and UGT2B7. We also confirmed the noninhibition of CYP3A4 and P-gp by other synthetic food dyes. Part of this inhibition depended upon the reaction of 1O2 originating on xanthene dyes by light irradiation, because inhibition was prevented by 1O2 quenchers. We studied the influence of superoxide dismutase and catalase on this inhibition by dyes and we found prevention of inhibition by superoxide dismutase but not catalase. This result suggests that superoxide anions, originating on dyes by light irradiation, must attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins on skin under lighting and may lead to rough skin.
Highlights
The study of drug metabolism started from the conjugation between glycine and benzoic acid to hippuric acid in horse urine by Wohler in 1824
The study of drug metabolism has advanced according to developments in chemistry and the chemical industry since the nineteenth century; drug-metabolizing enzymes did not originate from chemistry development but rather were developed to excrete natural substances of low molecular weight, mainly plant materials such as catechols, terpenoids, alkaloids, flavonoids, lignins, and amines, ingested by the body with five major nutrients in foods from when living things were created, 3.5 billion years ago or earlier [1]
We have investigated the induction of human UGT1A1 by bilirubin [5, 30,31,32,33,34], autoantibodies in autoimmune hepatitis patients [35,36,37,38], participation of human UGT1A6 in drug interaction between valproate and capbapenem antibiotics [39,40,41], structure-function relationships of some opioid derivatives for human UGT2B7 [42], and recent progress of the endogenous function of P-gp [43,44,45,46]
Summary
The study of drug metabolism started from the conjugation between glycine and benzoic acid to hippuric acid in horse urine by Wohler in 1824. Caffeine and chlorogenic acid are major constituents in coffee and are ingested and metabolized by so-called drug-metabolizing enzymes Many of these small materials should be excreted in urine from the kidneys and in bile from the liver after phase I and II drug-metabolizing enzymes and transporters react with them. These CYPs and UGTs are major protein constituents in microsomes and a few CYPs and UGTs might be coupled and co-operate with each other in membranes Most xenobiotics, such as drugs, nonnutrient substances of low molecular mass in foods, and pollutants, are absorbed and metabolized by phase I drug-metabolizing enzymes, followed by phase II enzymes, and excreted through transporters (phase III enzymes). In this review about safety testing of human-specific drug metabolites, we showed inhibition of xanthene food dyes for drug-metabolizing enzymes, summarized from our reports [27,28,29]. We have investigated the induction of human UGT1A1 by bilirubin [5, 30,31,32,33,34], autoantibodies in autoimmune hepatitis patients [35,36,37,38], participation of human UGT1A6 in drug interaction between valproate and capbapenem antibiotics [39,40,41], structure-function relationships of some opioid derivatives for human UGT2B7 [42], and recent progress of the endogenous function of P-gp [43,44,45,46]
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