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

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 Cmax 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

Mammalian Cytochrome P450-Dependent Metabolism of Polychlorinated Dibenzo-p-dioxins and Coplanar Polychlorinated Biphenyls

Polychlorinated dibenzo-p-dioxins (PCDDs) and coplanar polychlorinated biphenyls (PCBs) contribute to dioxin toxicity in humans and wildlife after bioaccumulation through the food chain from the environment. The authors examined human and rat cytochrome P450 (CYP)-dependent metabolism of PCDDs and PCBs. A number of human CYP isoforms belonging to the CYP1 and CYP2 families showed remarkable activities toward low-chlorinated PCDDs. In particular, human CYP1A1, CYP1A2, and CYP1B1 showed high activities toward monoCDDs, diCDDs, and triCDDs but no detectable activity toward 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-tetraCDD). Large amino acids located at putative substrate-recognition sites and the F-G loop in rat CYP1A1 contributed to the successful metabolism of 2,3,7,8-tetraCDD. Rat, but not human, CYP1A1 metabolized 3,3\u27,4,4\u27,5-pentachlorobiphenyl (CB126) to two hydroxylated metabolites. These metabolites are probably less toxic than is CB126, due to their higher solubility. Homology models of human and rat CYP1A1s and CB126 docking studies indicated that two amino acid differences in the CB126-binding cavity were important for CB126 metabolism. In this review, the importance of CYPs in the metabolism of dioxins and PCBs in mammals and the species-based differences between humans and rats are described. In addition, the authors reveal the molecular mechanism behind the binding modes of dioxins and PCBs in the heme pocket of CYPs

The configuration of the 17-hydroxy group variably influences the glucuronidation of -estradiol and epiestradiol by human UDP-glucuronosyltransferases. Drug Metab Dispos 36:2307–2315.

Abstract The glucuronidation of 17β-estradiol (β-estradiol) and 17α-estradiol (epiestradiol) was studied to elucidate how the orientation of the 17-OH group affects conjugation at the 3-OH or the 17-OH of either diastereomer. Recombinant human UDP-glucuronosyltransferases (UGTs) 1A1, 1A3, 1A7, 1A8 and 1A10 conjugated one or both diastereomers, mainly at the 3-OH. The activity of UGT1A4 was low and unique since it was directed merely towards the 17-OH of both aglycones. UGT1A10 exhibited particularly high estradiol glucuronidation activity, the rate and affinity of which were significantly higher in the case of β-estradiol than with epiestradiol. UGT1A9 did not catalyze estradiol glucuronidation but UGT1A9-catalyzed scopoletin glucuronidation was competitively inhibited by β-estradiol. UGTs 2B4, 2B7 and 2B17 exclusively conjugated the estradiols at the 17-OH position in a highly stereoselective fashion. UGT2B4 was specific for epiestradiol, UGT2B7 glucuronidated both diastereomers, with high affinity for epiestradiol, whereas UGT2B17 only glucuronidated β-estradiol. UGT2B15 glucuronidated both estradiols at the 3-OH, with a strong preference for epiestradiol. Human UGT2A1 and UGT2A2 glucuronidated both diastereoisomers at both hydroxyl groups. Microsomal studies revealed that human liver mainly yielded epiestradiol 17-O-glucuronide, human intestine primarily β-estradiol 3-O-glucuronide, while rat liver preferentially formed β-estradiol 17-O-glucuronide. Of the 3 recombinant rat UGTs that were examined in this study, rUGT2B1 was specific for the 17-OH of β-estradiol, rUGT2B2 did not catalyze estradiol glucuronidation, whereas rUGT2B3 exhibited high activity towards the 17-OH in both diastereoisomers. The results demonstrate that while many UGTs can catalyze estradiol glucuronidation, there are marked differences in their kinetics, regioselectivity and stereoselectivity