Effect Of Vanillin And Ethyl Vanillin On Cytochrome P450Activity In Vitro And In Vivo

Food safety is of extreme importance to human health. Vanillin and ethyl vanillin are the widely used food additives and spices in foods, beverages, cosmetics and drugs. Previous studies showed that vanillin is useful as anti-mutagen and anti-bacteria agent at high concentration of un-oxidized form to be medically effective, as well as antioxidant. So far, little is known about the effect of vanillin and ethyl vanillin on the activities of CYPs in vitro and in vivo. The drug interactions associated with induction or inhibition of CYP enzymes have been shown to be among the important factors in causing side effects in clinics. The objective of the present work was to evaluate the impact of vanillin and ethyl vanillin on the activities of CYP2C9, CYP2E1, CYP3A4, CYP2B6and CYP1A2in human liver microsome (HLM) in vitro, and impact on the activities of CYP1A2, CYP2C, CYP3A and CYP2E1in rat liver microsome (RLM) in vivo.In vitro method:The concentrations of vanillin/ethyl vanillin added to the incubations were ranged from8to128μM. After incubated with the optimal conditions, the activities of five CYP450enzymes (CYP2C9, CYP2E1, CYP3A4, CYP2B6and CYP1A2) were determined by HPLC. In vivo method:Male Wistar rats were orally administered by vanillin and ethyl Vanillin at three dosage levels(3mg/kg/day,15mg/kg/day and75mg/kg/day) for7consecutive days, then the activities of four CYP450enzymes (CYP3A,1A2,2E1and2C) were determined by Multifunction Microplate Reader and HPLC.Vanillin and ethyl vanillin had no significant effect on the five CYP-catalyzed reactions in HLM in vitro. Compared to the control, vanillin at low, medium and high doses caused19.4%,9.8%and22.6%decreases in CYP1A2-associated resorufin formation respectively, and caused63.7%,18.5%and34.9%increases in CYP2E1-associated p-nitrocatechol formation respectively, but the change caused by medium dose had no significant difference. Ethyl vanillin at low, medium and high doses caused17.2%,30.2%and19.0%decreases in CYP1A2-associated resorufin formation respectively, and caused16.4%,18.5%and30.8%increases in CYP2E1-associated p-nitrocatechol formation respectively. But the change of CYP1A2activity caused by high dose, and the change of CYP2E1activity caused by medium dose, had no significant difference.Results of this study showed that both vanillin and ethyl vanillin had no significant effect on the five CYP-catalyzed reactions in vitro. The in vivo results revealed that drug interaction between vanillin/ethyl vanillin and the CYP2E1/CYP1A2-metabolizing drugs might be possible, and also suggested that the application of the above additives in foods and drugs should not be unlimited so as to avoid the adverse interaction.