Evaluation of the inhibition of chlorophenols towards human cytochrome P450 3A4 and differences among various species.

Chlorophenols (CPs) are important pollutants detected frequently in the environment. This study intended to detect the inhibitory effects of fourteen CPs (2-CP, 3-CP, 4-CP, 4C2AP, 4C3MP, 2.4-DCP, 2.3.4-TCP, 2.4.5-TCP, 2.4.6-TCP, 3.4.5-TCP, 2.3.4.5-TECP, 2.3.4.6-TECP, 2.3.5.6-TECP and PCP) towards human liver cytochrome P450 3A4 (CYP3A4). Throughout the tests, testosterone was used as the probe substrate and CPs were used as inhibitors. A series of experiments (enzyme activity assays, preliminary screening tests, inhibition kinetics determination) were conducted to determine the inhibition of CPs towards human liver CYP3A4. CPs with the inhibitory effect >80% were selected for the inhibition evaluation in liver microsomes from different animal species (monkey, rat, dog, pig). The results showed that 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP inhibited the activities of CYP3A4 by 80.3%, 93.4%, 91.6%, respectively. Inhibition kinetics type were non-competitive and inhibition kinetics constant (Ki) values were 26.4 µM, 13.5 µM, and 8.8 µM for the inhibition of 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP towards human CYP3A4, respectively. Inhibition kinetics type was competitive and Ki value was 4.9 µM for the inhibition of 2.3.4-TCP towards CYP3A4 in Monkey liver microsomes (MyLMs). Inhibition kinetic types were non-competitive and Ki values were 8.1 µM and 28.7 µM for the inhibition of 3.4.5-TCP and 2.3.4.5-TECP towards CYP3A4 in MyLMs. Inhibition kinetic types were non-competitive and Ki values were 13.8 µM, 0.6 µM, and 6.1 µM for the inhibition of 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP towards CYP3A4 in Dog liver microsomes (DLMs), respectively. By comparing Ki values and inhibition kinetic types, the dog was the most suitable model to assess the inhibition of 2.3.4-TCP and 2.3.4.5-TECP towards CYP3A4, and monkey was the most suitable model to assess the inhibition of 3.4.5-TCP towards CYP3A4. In conclusion, our recent study on the inhibition of CPs towards CYP3A4 and species differences was important for further toxicological studies of CPs in human bodies.

Per- and polyfluoroalkyl substances display structure-dependent inhibition towards UDP-glucuronosyltransferases.

Per- and polyfluoroalkyl substances (PFASs) are a large group of chemicals and can be detected in environmental and human samples all over the world. Toxicity of existing and emerging PFASs will be a long-term source of concern. This study aimed to investigate structure-dependent inhibitory effects of 14 PFASs towards the activity of 11 UDP-glucuronosyltransferase (UGT) isoforms. In vitro UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was employed to determine the inhibition of PFASs towards different UGT isoforms. All the PFASs showed <75% of inhibition or stimulation effects on UGT1A3, UGT1A7, UGT1A9, UGT2B4, UGT2B7 and UGT2B17. However, PFASs showed broad inhibition on the activity of UGT1A1 and UGT1A8. The activity of UGT1A1 was inhibited by 98.8%, 98%, 79.9%, 77.1%, and 76.9% at 100 µmoL/L of perfluorodecanoic acid (PFDA), perfluorooctanesulfonic acid potassium salt (PFOS), perfluorotetradecanoic acid (PFTA), perfluorooctanoic acid (PFOA) and perfluorododecanoic acid (PFDoA), respectively. UGT1A8 was inhibited by 97.6%, 94.8%, 86.3%, 83.4% and 77.1% by PFDA, PFTA, perfluorooctadecanoic acid (PFOcDA), PFDoA and PFOS, respectively. Additionally, PFDA significantly inhibited UGT1A6 and UGT1A10 by 96.8% and 91.6%, respectively. PFDoA inhibited the activity of UGT2B15 by 88.2%. PFDA and PFOS exhibited competitive inhibition towards UGT1A1, and PFDA and PFTA showed competitive inhibition towards UGT1A8. The inhibition kinetic parameter (Ki) were 3.15, 1.73, 13.15 and 20.21 µmoL/L for PFDA-1A1, PFOS-1A1, PFDA-1A8 and PFTA-1A8, respectively. The values were calculated to be 0.3 µmoL/L and 1.3 µmoL/L for the in vivo inhibition of PFDA towards UGT1A1-and UGT1A8-catalyzed metabolism of substances, and 0.2 µmoL/L and 2.0 µmoL/L for the inhibition of PFOS towards UGT1A1 and the inhibition of PFTA towards UGT1A8, respectively. Molecular docking indicated that hydrogen bonds and hydrophobic interactions contributed to the interaction between PFASs and UGT isoforms. In conclusion, exposure to PFASs might inhibit the activity of UGTs to disturb metabolism of endogenous compounds and xenobiotics. The structure-related effects of PFASs on UGTs would be very important for risk assessment of PFASs.

Comparison of the inhibition potential of parthenolide and micheliolide on various UDP-glucuronosyltransferase isoforms.

Parthenolide (PTL) and micheliolide (MCL) are sesquiterpene lactones with similar structures, and both of them have been reported to exhibit multiple biochemical and pharmacological activities. This study aims to investigate the inhibition of these two compounds on the activity of UDP-glucuronosyltransferases (UGTs). In vitro incubation mixture for recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition kinetics (including inhibition type and parameters) were determined, and in silico docking was employed to elucidate the inhibition difference between PTL and MCL on UGT1A1. MCL showed no inhibition toward all the UGT isoforms, and PTL showed strong inhibition toward UGT1A1. The half-maximal inhibitory concentration (IC50) of PTL on the activity of UGT1A1 was determined to be 64.4 µM. Inhibition kinetics determination showed that PTL exerted noncompetitive inhibition toward UGT1A1, and the inhibition kinetic constant (Ki) was determined to be 12.1 µM. In silico docking method has been employed to show that hydrogen bonds between PTL and the activity cavity of UGT1A1 contributed to the stronger inhibition of PTL on the activity of UGT1A1 than MCL. In conclusion, PTL can more easily induce drug-drug interaction (DDI) with clinical drugs mainly undergoing UGT1A1-catalyzed glucuronidation.

Hydroxy metabolites of polychlorinated biphenyls (OH-PCBs) exhibit inhibitory effects on UDP-glucuronosyltransferases (UGTs).

Hydroxy metabolites of polychlorinated biphenyls (OH-PCBs) are important substance basis for the toxicity of PCBs. This study aims to investigate the inhibition of OH-PCBs on the activity of UDP-glucuronosyltransferases (UGTs), trying to elucidate the toxicity mechanism of PCBs from a new perspective. In vitrohuman recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used as the probe reaction. The number of chlorine atom can affect the inhibition potential of OH-PCBs towards different isoforms of UGTs, and complex structure-activity relationship was found for the inhibition of OH-PCBs on the activities of UGT isoforms. For the inhibition kinetic determination, 2'OHPCB106 and 4'OHPCB106 were selected as the representative OH-PCBs, and UGT1A1, 1A7, and 2B7 were chosen as the representative UGT isoforms. Competitive inhibition of 2'OHPCB106 and 4'OHPCB106 on the activities of UGT1A1, UGT1A7, and UGT2B7 was found. For 2'OHPCB106, the inhibition kinetic parameters (Ki) were calculated to be 0.4 µM for UGT1A1, 1.3 µM for UGT1A7, and 2.7 µM for UGT2B7, respectively. For 4'OHPCB106, Ki values were calculated to be 0.7 µM for UGT1A1, 6.8 µM for UGT1A7, and 4.8 µM for UGT2B7, respectively. In silico docking method was utilized to elucidate the inhibition difference of UGT1A1 by four OH-PCBs with similar structures (4'OHPCB9, 4'OHPCB26, 4'OHPCB112 and 4'OHPCB165). In conclusion, these data will be helpful for understanding the toxicity mechanisms of PCBs from a view of metabolic interference.

New insights for risks of chlorophenols (CPs) exposure: Inhibition of UDP-glucuronosyltransferases (UGTs).

Chlorophenols (CPs) are important pollutants extensively utilized in industry, agriculture and forestry. The present study aims to determine the inhibition of CPs on the activity of the important phase II drug-metabolizing enzymes (DMEs) UDP-glucuronosyltransferases (UGTs). 100 µM of fourteen CPs were used for preliminary screening using in vitro incubation. Furthermore, half inhibition concentration (IC50) and inhibition kinetics were determined for CPs with significant inhibition towards UGT isoforms. In silico docking was used to explain the inhibition difference among CPs. Multiple UGT isoforms were inhibited by CPs. In silico docking showed that higher free binding energy due to hydrophobic interactions of 2.4-Dichlorophenol (2.4-DCP) or 4-Chloro-3-methylphenol (4C3MP) with UGT1A9 contributed to stronger inhibition potential of 2.4-Dichlorophenol (2.4-DCP) or 4-Chloro-3-methylphenol (4C3MP) towards UGT1A9 than 4-CP. Pentachlorophenol (PCP) was chosen as the representative CPs to determine the IC50 value towards UGT1A6, UGT1A9 and UGT2B7. IC50 was calculated to be 0.33 µM, 0.24 µM and 31.35 µM for the inhibition of PCP towards UGT1A6, UGT1A9 and UGT2B7. PCP was demonstrated to show competitive inhibition towards UGT1A6, UGT1A9 and UGT2B7, and the inhibition kinetic parameters (Ki) was calculated to be 0.18 µM, 0.01 µM and 5.37 µM for the inhibition of PCP towards UGT1A6, UGT1A9 and UGT2B7. All these information will be beneficial for elucidating the risk of CPs exposure from a new perspective.

Inhibition of UDP-glucuronosyltransferases (UGTs) by phthalate monoesters.

Phthalate monoesters are important metabolites of phthalate esters (PAEs) which have been extensively utilized in industry. This study aims to investigate the inhibition of phthalate monoesters on the activity of various isoforms of UDP-glucuronosyltransferases (UGTs), trying to elucidate the toxicity mechanism of environmental endocrine disruptors from the new perspectives. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was employed to evaluate 8 kinds of phthalate monoesters on 11 sorts of main human UGT isoforms. 100 µM phthalate monoesters exhibited negligible inhibition towards the activity of UGT1A1, UGT1A3, UGT1A6, UGT1A8, UGT1A10, UGT2B4, UGT2B7, UGT2B15 and UGT2B17. The activity of UGT1A7 was strongly inhibited by monoethylhexyl phthalate (MEHP), but slightly inhibited by all the other phthalate monoesters. UGT1A9 was broadly inhibited by monobenzyl phthalate (MBZP), monocyclohexyl phthalate (MCHP), MEHP, monohexyl phthalate (MHP) and monooctyl phthalate (MOP), respectively. MEHP exhibited competitive inhibition towards UGT1A7, and MBZP, MCHP, MEHP, MHP and MOP showed competitive inhibition towards UGT1A9. The inhibition kinetic parameters (Ki) were calculated to be 11.25 µM for MEHP-UGT1A7, and 2.13, 0.09, 1.17, 7.47, 0.16 µM for MBZP-UGT1A9, MCHP-UGT1A9, MEHP-UGT1A9, MHP-UGT1A9, MOP-UGT1A9, respectively. Molecular docking indicated that both hydrogen bonds formation and hydrophobic interactions significantly contributed to the interaction between phthalate monoesters and UGT isoforms. All these information will be beneficial for understanding the adverse effects of PAEs.

The inhibition of UDP-glucuronosyltransferases (UGTs) by tetraiodothyronine (T4) and triiodothyronine (T3).

1. UDP-glucuronosyltransferases (UGTs) are important drug-metabolizing enzymes (DMEs) catalyzing the glucuronidation elimination of various xenobiotics and endogenous substances. Endogenous substances are important regulators for the activity of various UGT isoforms. Triiodothyronine (T3) and thyroxine (T4) are important thyroid hormones essential for normal cellular differentiation and growth. The present study aims to elucidate the inhibition behavior of T3 and T4 on the activity of UGT isoforms. 2. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to screen the inhibition potential of T3 and T4 on the activity of various UGT isoforms. Initial screening results showed that T4 exerted stronger inhibition potential than T3 on the activity of various UGT isoforms at 100 µM. Inhibition kinetics was determined for the inhibition of T4 on the representative UGT isoforms, including UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7. The results showed that T4 competitively inhibited the activity of UGT1A1, -1A3, -1A7, 1A10 and -2B7, and noncompetitively inhibited the activity of UGT1A8. The inhibition kinetic parameters were calculated to be 1.5, 2.4, 11, 9.6, 4.8 and 3.0 µM for UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7, respectively. In silico docking method was employed to demonstrate why T4 exerted stronger inhibition than T3 towards UGT1A1. Stronger hydrogen bonds and hydrophobic interaction between T4 and activity cavity of UGT1A1 than T3 contributed to stronger inhibition of T4 towards UGT1A1. 3. In conclusion, more clinical monitoring should be given for the patients with the elevation of T4 level due to stronger inhibition of UGT isoforms-catalyzed metabolism of drugs or endogenous substances by T4.

Inhibitory effects of fifteen phthalate esters in human cDNA-expressed UDP-glucuronosyltransferase supersomes.

Phthalate esters (PAEs) have been extensively used in industry as plasticizers and there remains concerns about their safety. The present study aimed to determine the inhibition of phthalate esters (PAEs) on the activity of the phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone was used to investigate the inhibition potentials of PAEs towards various s UGTs. PAEs exhibited no significant inhibition of UGT1A1, UGT1A3, UGT1A8, UGT1A10, UGT2B15, and UGT2B17, and limited inhibition of UGT1A6, UGT1A7 and UGT2B4. However, UGT1A9 was strongly inhibited by PAEs. In silico docking demonstrated a significant contribution of hydrogen bonds and hydrophobic interactions contributing to the inhibition of UGT by PAEs. The Ki values were 15.5, 52.3, 23.6, 12.2, 5.61, 2.79, 1.07, 22.8, 0.84, 73.7, 4.51, 1.74, 0.58, 6.79, 4.93, 6.73, and 7.23 µM for BBOP-UGT1A6, BBZP-UGT1A6, BBOP-UGT1A7, BBZP-UGT1A7, DiPP-UGT1A9, DiBP-UGT1A9, DCHP-UGT1A9, DBP-UGT1A9, BBZP-UGT1A9, BBOP-UGT1A9, DMEP-UGT1A9, DPP-UGT1A9, DHP-UGT1A9, DiBP-UGT2B4, DBP-UGT2B4, DAP-UGT2B4, and BBZP-UGT2B4, respectively. In conclusion, exposure to PAEs might influence the metabolic elimination of endogenous compounds and xenobiotics through inhibiting UGTs.

In Vitro Comparative Study of the Inhibitory Effects of Mangiferin and Its Aglycone Norathyriol towards UDP-Glucuronosyl Transferase (UGT) Isoforms.

Mangiferin (MGF), the predominant constituent of extracts of the mango plant Mangifera Indica L., has been investigated extensively because of its remarkable pharmacological effects. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to investigate the inhibition of mangiferin and aglycone norathyriol towards various isoforms of UGTs in our study, which evaluated the inhibitory capacity of MGF and its aglycone norathyriol (NTR) towards UDP-glucuronosyltransferase (UGT) isoforms. Initial screening experiment showed that deglycosylation of MGF into NTR strongly increased the inhibitory effects towards almost all the tested UGT isoforms at a concentration of 100 µM. Kinetic experiments were performed to further characterize the inhibition of UGT1A3, UGT1A7 and UGT1A9 by NTR. NTR competitively inhibited UGT1A3, UGT1A7 and UGT1A9, with an IC50 value of 8.2, 4.4, and 12.3 µM, and a Ki value of 1.6, 2.0, and 2.8 µM, respectively. In silico docking showed that only NTR could dock into the activity cavity of UGT1A3, UGT1A7 and UGT1A9. The binding free energy of NTR to UGT1A3, 1A7, 1A9 were -7.4, -7.9 and -4.0 kcal/mol, respectively. Based on the inhibition evaluation standard ([I]/Ki < 0.1, low possibility; 0.1 < [I]/Ki < 1, medium possibility; [I]/Ki > 1, high possibility), an in vivo herb-drug interaction between MGF/NTR and drugs mainly undergoing UGT1A3-, UGT1A7- or UGT1A9-catalyzed metabolism might occur when the plasma concentration of NTR is above 1.6, 2.0 and 2.8 µM, respectively.

The inhibition of UDP-glucuronosyltransferases (UGTs) by vitamin A.

1. The exposed level of vitamin A in plasma might be exceeded due to the both inadvertent and clinical utilization. The adverse effects of vitamin A have been frequently reported, however, the mechanism remains unclear. The inhibition of vitamin A on the activity of UDP-glucuronosyltransferases (UGTs) was determined using in vitro incubation system to explain the adverse effects of vitamin A from a new perspective. 2. UGT supersomes catalyzed glucuronidation of 4-methylumbelliferone (4-MU), trifluoperazine (TFP), and cotinine was used as the probe reaction to evaluate the inhibition of vitamin A toward UGT isoforms, and 100 µM of vitamin A significantly inhibited the activity of all the tested UGT isoforms. Vitamin A exerted competitive inhibition on the activity of UGT1A1, 2B4, 2B7, and 2B15, and the inhibition kinetic parameters (Ki) were calculated to be 31.1, 16.8, 2.2, and 11.6 µM for UGT1A1, 2B4, 2B7, and 2B15. In silico docking method was used to try to elucidate the inhibition mechanism of vitamin A toward UGT2B7. The results showed the significant contribution of hydrogen bonds and hydrophobic interaction on the UGT2B7 inhibition by vitamin A. 3. The present study provides a new perspective for the adverse effects of vitamin A through reporting the inhibition of vitamin A on the activity of important phase II drug-metabolizing enzymes UGTs, which benefits our deep understanding of mechanism of vitamin A's adverse effects when high exposure of vitamin A occurs.

[The inhibition of carboxylesterases by praeruptorin C, D and E].

Praeruptorin C (PC), D (PD) and E (PE) are important compounds extracted from Peucedanum praeruptorum DUNN and have been reported to exert multiple pharmacological activities. The present study is purposed to determine the inhibition of PC, PD and PE on the activity of important phase I metabolic enzymes ­ carboxylesterases (CES). In vitro human liver microsomes (HLM) incubation system was used to determine the inhibition potential of PC, PD and PE on the activity of CES1 and CES2. Inhibition behaviour was determined, and in vitro-in vivo extrapolation was performed by using the combination of in vitro inhibition kinetic parameter (K(I)) and in vivo exposure level of PD. PD exhibited the strongest inhibition on the activity of CES1, with 81.7% activity inhibited by 100 µmol·L(-1) of PD. PD noncompetitively inhibited the activity of CES1 with the K(I) to be 122.2 µmol·L(-1), indicating inhibition potential of PD towards CES1 in vivo. Therefore, closely monitoring the endogenous metabolic disorders caused by PD and interaction between PD and drugs mainly undergoing CES1-catalyzed metabolism is very necessary.

Role of the lipid-regulated NF-κB/IL-6/STAT3 axis in alpha-naphthyl isothiocyanate-induced liver injury.

Alpha-naphthyl isothiocyanate (ANIT)-induced liver damage is regarded as a useful model to study drug-induced cholestatic hepatitis. Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry (UPLC-ESI-QTOF MS)-based metabolomics revealed clues to the mechanism of ANIT-induced liver injury, which facilitates the elucidation of drug-induced liver toxicity. 1-Stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:0) and 1-oleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:1) were significantly increased in serum from ANIT-treated mice, and this increase resulted from altered expression of genes encoding the lipid metabolism enzymes Chka and Scd1. ANIT also increased NF-κB/IL-6/STAT3 signaling, and in vitro luciferase reporter gene assays revealed that LPC 18:0 and LPC 18:1 can activate NF-κB in a concentration-dependent manner. Activation of PPARα through feeding mice a Wy-14,643-containing diet (0.1%) reduced ANIT-induced liver injury, as indicated by lowered ALT and AST levels, and liver histology. In conclusion, the present study demonstrated a role for the lipid-regulated NF-κB/IL-6/STAT3 axis in ANIT-induced hepatotoxicity, and that PPARα may be a potential therapeutic target for the prevention of drug-induced cholestatic liver injury.

The Inhibition of UDP-Glucuronosyltransferase (UGT) Isoforms by Praeruptorin A and B.

Praeruptorin A (PA) and B (PB) are two important compounds isolated from Bai-hua Qian-hu and have been reported to exert multiple biochemical and pharmacological activities. The present study aims to determine the inhibition of PA and PB on the activity of important phase II drug-metabolizing enzymes uridine 5'-diphospho-glucuronosyltransferase (UGTs) isoforms. In vitro UGT incubation system was used to determine the inhibition potential of PA and PB on the activity of various UGT isoforms. In silico docking was performed to explain the inhibition difference between PA and PB towards the activity of UGT1A6. Inhibition behaviour was determined, and in vitro-in vivo extrapolation was performed by using the combination of in vitro inhibition kinetic parameter (Ki ) and in vivo exposure level of PA. Praeruptorin A (100 µM) exhibited the strongest inhibition on the activity of UGT1A6 and UGT2B7, with 97.8% and 90.1% activity inhibited by 100 µM of PA, respectively. In silico docking study indicates the significant contribution of hydrogen bond interaction towards the stronger inhibition of PA than PB towards UGT1A6. Praeruptorin A noncompetitively inhibited the activity of UGT1A6 and competitively inhibited the activity of UGT2B7. The inhibition kinetic parameter (Ki ) of PA towards UGT1A6 and UGT2B7 was calculated to be 1.2 and 3.3 µM, respectively. The [I]/Ki value was calculated to be 15.8 and 5.8 for the inhibition of PA on UGT1A6 and UGT2B7, indicating high inhibition potential of PA towards these two UGT isoforms in vivo. Therefore, closely monitoring the interaction between PA and drugs mainly undergoing UGT1A6 or UGT2B7-catalyzed metabolism is very necessary. Copyright © 2016 John Wiley & Sons, Ltd.

Inhibition behavior of fructus psoraleae's ingredients towards human carboxylesterase 1 (hCES1).

1. Fructus psoraleae (FP) is the dried ripe seeds of Psoralea corylifolia L. (Fabaceae) widely used in Asia, and has been reported to exert important biochemical and pharmacological activities. The adverse effects of FP remain unclear. The present study aims to determine the inhibition of human carboxylesterase 1 (CES1) by FP's major ingredients, including neobavaisoflavone, corylifolinin, coryfolin, psoralidin, corylin and bavachinin. 2. The probe substrate of CES1 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) was derived from 2-(2-hydroxy-3-methoxyphenyl) benzothiazole (HMBT), and human liver microsomes (HLMs)-catalyzed BMBT metabolism was used to phenotype the activity of CES1. In silico docking method was employed to explain the inhibition mechanism. 3. All the tested compounds exerted strong inhibition towards the activity of CES1 in a concentration-dependent behavior. Furthermore, the inhibition kinetics was determined for the inhibition of neobavaisoflavone, corylifolinin, coryfolin, corylin and bavachinin towards CES1. Both Dixon and Lineweaver-Burk plots showed that neobavaisoflavone, corylifolinin, coryfolin and corylin noncompetitively inhibited the activity of CES1, and bavachinin competitively inhibited the activity of CES1. The inhibition kinetic parameters (Ki) were calculated to be 5.3, 9.4, 1.9, 0.7 and 0.5 µM for neobavaisoflavone, corylifolinin, coryfolin, corylin and bavachinin, respectively. In conclusion, the inhibition behavior of CES1 by the FP's constituents was given in this article, indicating the possible adverse effects of FP through the disrupting CES1-catalyzed metabolism of endogenous substances and xenobiotics.

New insights into the risk of phthalates: Inhibition of UDP-glucuronosyltransferases.

Wide utilization of phthalates-containing products results in the significant exposure of humans to these compounds. Many adverse effects of phthalates have been documented in rodent models, but their effects in humans exposed to these chemicals remain unclear until more mechanistic studies on phthalate toxicities can be carried out. To provide new insights to predict the potential adverse effects of phthalates in humans, the recent study investigated the inhibition of representative phthalates di-n-octyl ortho-phthalate (DNOP) and diphenyl phthalate (DPhP) towards the important xenobiotic and endobiotic-metabolizing UDP-glucuronosyltransferases (UGTs). An in vitro UGTs incubation system was employed to study the inhibition of DNOP and DPhP towards UGT isoforms. DPhP and DNOP weakly inhibited the activities of UGT1A1, UGT1A7, and UGT1A8. 100 µM of DNOP inhibited the activities of UGT1A3, UGT1A9, and UGT2B7 by 41.8% (p < 0.01), 45.6% (p < 0.01), and 48.8% (p < 0.01), respectively. 100 µM of DPhP inhibited the activity of UGT1A3, UGT1A6, and UGT1A9 by 81.8 (p < 0.001), 49.1% (p < 0.05), and 76.4% (p < 0.001), respectively. In silico analysis was used to explain the stronger inhibition of DPhP than DNOP towards UGT1A3 activity. Kinetics studies were carried our to determine mechanism of inhibition of UGT1A3 by DPhP. Both Dixon and Lineweaver-Burk plots showed the competitive inhibition of DPhP towards UGT1A3. The inhibition kinetic parameter (Ki) was calculated to be 0.89 µM. Based on the [I]/Ki standard ([I]/Ki < 0.1, low possibility; 1>[I]/Ki > 0.1, medium possibility; [I]/Ki > 1, high possibility), these studies predicted in vivo drug-drug interaction might occur when the plasma concentration of DPhP was above 0.089 µM. Taken together, this study reveales the potential for adverse effects of phthalates DNOP and DPhP as a result of UGT inhibition.

[Study on the status and related socio-psychological factors of maternal depression among high-risk pregnancy women in Harbin city].

OBJECTIVE: This study aimed to investigate the depression status among high-risk pregnancy women, and to analyze its relevant social and psychological factors. METHODS: A total of 42 high-risk pregnancy women and 40 normal pregnancy women in a teaching hospital in Harbin city were followed up at time points of 32 - 36 weeks pregnancy, one week before labor, one week postpartum, and six weeks postpartum, respectively. During follow-up, the basic situation, social psychosocial factors of pregnancy women were collected and the depression of pregnancy women was measured by self-designed questionnaire and self-rating depression scale. The Edinburgh Postnatal Depression Scale (EPDS) was applied at timepoint of one week postpartum. Single factor analysis and the unconditional multivariate logistic regression were applied for analyzing the on the related social-psychosocial factors among high-risk pregnancy women. RESULTS: The age of high-risk pregnancy women was (31.0±5.6), and the age of normal pregnancy women was (30.5±3.8) (t=0.169, P>0.05). The results showed that the depression rate in high-risk pregnancy women was 45.2% (19/42), which was 25.0% (10/40) in normal pregnancy women, the difference was significant (χ2=3.671, P=0.045). The depression rates at different time points were 30.9% (13/42), 42.9% (18/42), 23.8% (10/42), 26.2% (11/42) in high-risk pregnancy women respectively, and 25.0% (10/40), 15.0% (6/40), 20.0% (8/40), 17.5% (7/40) in the control group respectively, the difference of the depression rates among groups at one week before labor was significant (χ2=7.680, P<0.01), the difference among groups at 32-36 weeks pregnancy (χ2=0.133, P=0.80), at one week postpartum (χ2=0.174, P=0.79) and at six weeks postpartum (χ2=0.903, P=0.43) were not significant. At one week postpartum and six weeks postpartum periods, the EPDS depression rate were 12.5% (4/32), 30.4% (7/23) in case group respectively, 8.3% (3/36), 22.9% (8/35) in control group respectively, the difference were not significant (χ2=0.319, 0.416, P=0.573, 0.519). There were significantly associations between the depression mood of one week before labor and the depressive symptoms of six weeks postpartum in both groups (r=0.824, 0.677, both P values were <0.05). The risk factors for maternal depression among high-risk pregnancy women were not ready for production (OR=2.73, P<0.01) and fearing of childbirth safety (OR=2.89, P<0.01). CONCLUSION: The depression date of high-risk pregnancy was high, especially at the time point one week before labor. Risk factors of maternal depression among high-risk pregnancy were "not ready for production" and "fear of childbirth safety".