engleski

Biotransformation of tangeretin mediated by human liver cytochrome P450 enzymes

Tangeretin is a flavonoid found in citrus plants. Structurally, it presents an O-polymethoxylated derivative of flavone. It has been extensively studied due to the possible beneficial effects on human health that include neuroprotective, anti-inflammatory, antiasthmatic, antidiabetic, anticancer and other properties. Although metabolism and pharmacokinetics of tangeretin has been studied, due to numerous metabolic products, not all metabolic reactions of tangeretin have been well characterized. Thus, the objective of this work was to characterize tangeretin metabolism mediated by cytochromes P450. For this purpose, human liver microsomes (HLM) and recombinant cytochrome P450 enzymes were used. Metabolism was monitored by liquid chromatography coupled with mass spectrometry (electron spray ionization, time of flight detection) for metabolites determination and diode array detector for quantification. Tangeretin generated more than 10 metabolites in the incubations with HLM. The largest number of detected metabolites refers to single and double demethylated tangeretin derivatives in various combinations and at different positions on the rings A and B. Two major metabolites, most commonly found in tangeretin incubations with HLM, were indirectly identified based on data obtained by LC-MS/MS analysis. MS/MS spectra showed a loss of -14.01564 Da on the ring B with the retention time of 9.52 min. Since only one methoxy group at position 4' is present in the tangeretin ring structure B, this metabolite was characterized as a 4'-demethylated tangeretin derivative, i.e., 4'-hydroxy-5, 6, 7, 8-tetramethoxyflavone. Similarly, the structure of the second most commonly found metabolite detected at 7.83 min showed a mass increase of 1.9799 Da on the ring B, indicating demethylation at the 4' position and hydroxylation at the positions 3' and the formation of 3', 4'-dihydroxy-5, 6, 7, 8-tetramethoxyflavone. Tangeretin metabolism was mediated by CYP1A2, CYP2D6, and CYP3A4 enzymes. Based on the amount of metabolite produced, it can be concluded that the most important enzymes are CYP1A2 and CYP3A4.

tangeretin, cytochrome P450 enzymes, metabolism

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