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Flavonoidi su heterogena skupina fenolnih spojeva koje sintetiziraju biljke, a ljudi ih unose putem voća i povrća. Osnovni skelet čine dva benzenska prstena povezana piranskim prstenom, a daljnje se razlike temelje na postojanju i raspodjeli dodatnih hidroksilnih i metilnih skupina. Interes za proučavanje flavonoida porastao je spoznajom o njihovom djelovanju kao antioksidansa te kardioprotektivnom, protuupalnom ili pak antivirusnom djelovanju. S farmakološkog gledišta ističu se zbog mogućih interakcija s enzimima koji metaboliziraju ksenobiotike, a to su u najvećem postotku enzimi superporodice citokroma P450. Postoje studije koje pokazuju da je biotransformacija pojedinih flavonoida posredovana CYP enzimima, a flavonoidi na njih mogu imati inhibicijski ili aktivacijski učinak. Stoga je potrebno detaljno istraţiti put metabolizma flavonoida i tako predvidjeti medikacijske pogreške koje mogu nastati ukoliko se pacijent liječi lijekom čiji je put metabolizma uključuje enzime koji također metabolizira flavonoide unosene kroz prehrambene namirnice ili kao dodatak prehrani. Ispitano je jedanaest različitih flavonoida koji su prethodnim probiranjem pokazali metabolizam u reakciji kataliziranoj CYP enzimima. LC-MS je kromatografska metoda koja nam daje uvid u postojanje metabolita jer osigurava informacije o molekulskoj masi i strukturi spoja, identifikaciji i kvantifikaciji pojedinih komponenti uzorka. Potvrdili smo identitet metabolita za četiri flavonoida, a nastali su reakcijama oksigenacije koje posreduje citokrom P450 2D6. Navedeni enzim u reakciji sa 7-hidroksiflavonom i galanginom daje hidroksilirane metabolite, u reakciji hidroksilacije s akacetinom daje novi flavonoid apigenin, a u reakcijama demetilacije s tangeretinom daje četiri različita metabolita, od kojih je jedan demetiliran na dvije pozicije. Flavonoids are a heterogeneous group of phenolic compounds that are biosynthesize by plants, and people ingest them through fruits and vegetables. The basic flavonoid skeleton consists of two benzene rings connected by a pyran. Further differences are based on the existence and distribution of additional hydroxyl and methyl groups. The interest in the study of flavonoids has increased with the knowledge of their action as antioxidants and cardioprotective, anti-inflammatory or antiviral activity. From a pharmacological point of view, they are interesting due to possible interactions with enzymes that metabolize xenobiotics, which are in the highest percentage memebers of cytochromes P450 superfamily. There are studies that show that biotransformation of certain flavonoids is mediated by CYP enzymes, and flavonoids may have an inhibitory or activating effect. Therefore, it is necessary to thoroughly explore the path of flavonoid metabolism and thus to predict medical errors that may arise if a patient is treated with a drug whose metabolic pathways includes an enzyme that also metabolizes flavonoids that are introduced through food or nutritional supplements. Eleven different flavonoids were tested, which by previous screening demonstrated the metabolism catalyzed by CYP enzymes. LC-MS is a chromatographic method that gives us an insight into the existence of a metabolite because it provides information on the molecular weight and structure of the compound, the identification and quantification of the individual sample components. We confirmed the identity of the metabolites for four flavonoids, and they were generated by cytochrome P450 2D6. This enzyme in the reaction with 7-hydroxyphenol and galangine gives hydroxylated metabolites, in the reaction with acacetin hydroxylation gives a new flavonoid apigenin, and in the reactions of tangerine demethylation it gives four different metabolites, one of which is demethylated in two positions. With regard to the cytochrome P450 2D6 polymorphisms and existence of four phenotypes that differ in the rate of biotransformation of drugs, these results are important because we can predict the potential drug-flavonoid interaction and providing a good therapeutic effect of the drug when combinde with flavonoids.

Cytochrome P450 enzyme debrisoquine 4-hydroxylase, responsible for the metabolism of different classes of drugs and other chemical substances, exhibits genetic polymorphism with great interindividual and interethnic differences in metabolic capacity. The activity of enzyme ranges from very expressed, rapid, to total absence of activity. Up to 7% of Caucasians may demonstrate ultrarapid metabolism--UEM of debrisoquine and other drugs, substrates of debrisoquin hydroxylase, due to inheritance of multiplicate functional CYP2D6 gene, causing an increased amount of enzyme to be expressed. Identification of subjects with ultrarapid metabolism is of potential clinical value for optimization of therapy and avoidance of therapeutic failure due to inadequate dosage. In our study we wanted to determine the prevalence of UEM genotype in Croatian population applying long-PCR method. We found a 4% prevalence of ultrarapid metabolizers with multiplicated CYP2D6 gene.