Abstract
Flavonoids are known to undergo phase II metabolism and produce metabolites with similar or stronger biological effects compared to the parent flavonoids. However, the limited cellular uptake and bioavailability restrict their clinical use. We synthesized phloridzin docosahexaenoate (PZ-DHA), a novel fatty acid ester of polyphenol, through an acylation reaction with the aim of increasing the cellular availability and stability of the parent biomolecules, phloridzin (PZ) and docosahexaenoic acid (DHA). Here, we report metabolites and pharmacokinetic parameters of PZ-DHA, determined using ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. PZ-DHA was taken-up by human (MDA-MB-231, MDA-MB-468, and MCF-7) and mouse (4T1) mammary carcinoma and human non-malignant mammary epithelial cells (MCF-10A) in cellular uptake assays. Our results suggested that the acylation improves the cellular uptake of PZ and stability of DHA within cells. In mouse hepatic microsomal assays, two major glucuronides of PZ-DHA, PZ-DHA-4-O-glucuronide and PZ-DHA-4′-O-glucuronide (MW = 923.02 g/mol), were detected. One tri-methylated- (4,4′,6′-O-trimethyl-PZ-DHA) (MW = 788.88 g/mol) and one di-sulphated- (PZ-DHA-4,4′-O-disulphide) PZ-DHA metabolite (MW = 906.20 g/mol) were also identified. Intraperitoneal injections of PZ-DHA (100 mg/kg) into Balb/c female mice was rapidly absorbed with a serum Cmax and Tmax of 23.7 µM and 60 min, respectively, and rapidly eliminated (t1/2 = 28.7 min). PZ-DHA and its metabolites are readily distributed throughout the body (Vd = 57 mL) into many organs. We identified in vitro and in vivo metabolites of PZ-DHA, which could be tested for potential use to treat diseases such as cancer in multiple organ systems.
Highlights
Flavonoids are known to undergo phase II metabolism and produce metabolites with similar or stronger biological effects compared to the parent flavonoids
The rationale for conjugating PZ with docosahexaenoic acid (DHA) through an acylation reaction was to improve the cellular uptake and stability of PZ and DHA, respectively. This hypothesis was tested by conducting cellular uptake experiments of PZ, DHA, and phloridzin docosahexaenoate (PZ-DHA) using mammary carcinoma cells and non-malignant mammary epithelial cells
Park et al showed that, following initial metabolism, DHA is esterified into cell lipids and retroconversion of DHA (22: 6n-3) to EPA (20: 5n-3) is five- to six-fold greater in non-neural cells compared to neural cells[22]
Summary
Flavonoids are known to undergo phase II metabolism and produce metabolites with similar or stronger biological effects compared to the parent flavonoids. Phase I biotransformation (often referred to as phase I metabolism) includes de novo formation or exposure of functional groups on drugs/xenobiotics, resulting in increased hydrophilicity and/or polarity These reactions are governed by cytochrome-p450 (CYP450) enzymes acting as monooxygenases, dioxygenases, and h ydrolases[7,8]. The clinical applications of flavonoids are restricted by their poor cellular uptake and bioavailability; attempts have been made to synthesize flavonoid derivatives, aiming to overcome these limitations[15] With this objective in mind, phloridzin docosahexaenoate (PZ-DHA) was synthesized by acylation of phloridzin (PZ), a flavonoid precursor, with docosahexanoic acid (DHA), an omega-3-fatty acid, through an enzyme-catalyzed esterification reaction[16]. The biological fate of PZ-DHA was investigated following the intraperitoneal administration of PZ-DHA to Balb/c female mice
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