8-Prenylnaringenin tissue distribution and pharmacokinetics in mice and its binding to human serum albumin and cellular uptake in human embryonic kidney cells

Abstract

8-Prenylnaringenin (8-PN), a hop flavonoid, is a promising food substance with health benefits. Compared with nonprenylated naringenin, 8-PN exhibits stronger estrogenic activity and prevents muscle atrophy. Moreover, 8-PN prevents hot flushes and bone loss. Considering that prenylation reportedly improves the bioavailability of flavonoids, we compared the parameters related to the bioavailability [pharmacokinetics and tissue distribution in C57/BL6 mice, binding affinity to human serum albumin (HSA), and cellular uptake in HEK293 cells] of 8-PN and its mother (non-prenylated) compound naringenin. C57/BL6 mice were fed an 8-PN or naringenin mixed diet for 22 days. The amount of 8-PN (nmol/g tissue) in the kidneys (16.8 ± 9.20), liver (14.8 ± 2.58), muscles (3.33 ± 0.60), lungs (2.07 ± 0.68), pancreas (1.80 ± 0.38), heart (1.71 ± 0.27), spleen (1.36 ± 0.29), and brain (0.31 ± 0.09) was higher than that of naringenin. A pharmacokinetic study in mice demonstrated that the C _max of 8-PN (50 mg/kg body weight) was lower than that of naringenin; however, the plasma concentration of 8-PN 8 h after ingestion was higher than that of naringenin. The binding affinity of 8-PN to HSA and cellular uptake in HEK293 cells were higher than those of naringenin. 8-PN bioavailability features assessed in mouse or human model experiments were obviously different from those of naringenin.

Keywords: 8‐prenylnaringenin; naringenin; pharmacokinetics; serum albumin; tissue accumulation.

FIGURE 1

Structures of 8‐PN (a) and naringenin (b)

FIGURE 2

Plasma concentrations of 8‐PN and naringenin after oral administration to mice. Each flavonoid was orally administered at 50 mg/kg BW in a single dose via oral gavage. Plasma samples were collected at 0.5, 1, 2, 4, 8, 24, and 48 h after administration. Inset represents a duplicated enlarged graph of the results from 4 to 48 h. The plasma concentrations of each flavonoid were determined using HPLC–UV after deconjugation treatment. Closed triangle: naringenin, closed square: 8‐PN. Data are presented as the mean ± SE (n = 5). Asterisks indicate significant differences between naringenin and 8‐PN at the same time points as determined by using the Mann–Whitney U test (*p < .05 and **p < .01, respectively)

FIGURE 3

Competition profiles of 8‐PN and 8‐PN‐7G for site I in HSA using the site‐selective HSA‐binding fluorescent probe DNSA. Data are calculated as the competitive inhibition rate (%) of DNSA with flavonoids (n = 3, mean ± SE)

FIGURE 4

Uptake of 8‐PN and naringenin by HEK293 cells. Cells seeded on 60‐mm dishes were used. Cells were treated with (a) naringenin (N) or 8‐PN (10 µM) for 1 h. Data are presented as the mean ± SE (n = 6). (b) Cells were treated with NaN₃ (100 µM) for 15 min. Then, 8‐PN (10 µM) was added to cells for 1 h. Flavonoid content was quantified using HPLC–UV analysis. Data are presented as the mean ± SE (n = 3). Asterisks indicate significant differences as determined by using the Mann–Whitney U test (**p < .01)