Influences of Realgar-Indigo naturalis, A Traditional Chinese Medicine Formula, on the Main CYP450 Activities in Rats Using a Cocktail Method.

The purpose of this work was to study the influences of Realgar-Indigo naturalis (RIF) and its principal element realgar on 4 main cytochrome P450 enzymes activities in rats. A simple and efficient cocktail method was developed to detect the four probe drugs simultaneously. In this study, Wistar rats were administered intragastric RIF and realgar for 14 days; mixed probe drugs were injected into rats by caudal vein. Through analyzing the pharmacokinetic parameter of mixed probe drugs in rats, we can calculate the CYPs activities. The results showed that RIF could inhibit CYP1A2 enzyme activity and induce CYP2C11 enzyme activity significantly. Interestingly, in realgar high dosage group, CYP3A1/2 enzyme activity was inhibited significantly, and different dosage of realgar manifested a good dose-dependent manner. The RIF results indicated that drug coadministrated with RIF may need to be paid attention in relation to drug-drug interactions (DDIs). Realgar, a toxic traditional Chinese medicine (TCM), does have curative effect on acute promyelocytic leukemia (APL). Its toxicity studies should be focused on. We found that, in realgar high dosage group, CYP3A1/2 enzymes activity was inhibited. This phenomenon may explain its potential toxicity mechanism.

Probing the reactivity of microhydrated α-nucleophile in the anionic gas-phase S(N)2 reaction.

To probe the kinetic performance of microsolvated α-nucleophile, the G2(+)M calculations were carried out for the gas-phase S(N)2 reactions of monohydrated and dihydrated α-oxy-nucleophiles XO(-)(H2O)(n = 1,2) (X = HO, CH3O, F, Cl, Br), and α-sulfur-nucleophile, HSS(-)(H2O)(n = 1,2), toward CH3Cl. We compared the reactivities of hydrated α-nucleophiles to those of hydrated normal nucleophiles. Our calculations show that the α-effect of monohydrated and dihydrated α-oxy-nucleophiles will become weaker than those of unhydrated ones if we apply a plot of activation barrier as a function of anion basicity. Whereas the enhanced reactivity of monohydrated and dihydrated ROO(-) (R = H, Me) could be observed if compared them with the specific normal nucleophiles, RO(-) (R = H, Me). This phenomena can not be seen in the comparisons of XO(-)(H2O)(n = 1,2) (X = F, Cl, Br) with ClC2H4O(-)(H2O)(n = 1,2), a normal nucleophile with similar gas basicity to XO(-)(H2O)(n = 1,2). These results have been carefully analyzed by natural bond orbital theory and activation strain model. Meanwhile, the relationships between activation barriers with reaction energies and the ionization energies of α-nucleophile are also discussed.

Concerted or stepwise mechanism? New insight into the water-mediated neutral hydrolysis of carbonyl sulfide.

The water-mediated neutral hydrolysis mechanism of carbonyl sulfide (OCS) has been re-examined using the hybrid supramolecule/continuum models with n = 2-8 explicit water cluster at the level of MP2(fc)(CPCM)/6-311++G(d,p)//MP2(fc)(CPCM)/6-31+G(d). Present calculations indicate that the potential energy surface in water solution is different from the one in the gas-phase, and only stepwise mechanism is observed in aqueous solution, i.e., monothiocarbonic acid (H2CO2S) is formed via monothiocarbonate (OCSOH(-), MTC) and its counterion, protonated water cluster, (H2O)nH3O(+). The predicted rate-determining step (RDS) barrier for the stepwise mechanism in water solution, about 90 kJ/mol, shows good agreement with the experimental values, 83.7-96.2 kJ/mol using six- or eight-water model including two cooperative water molecules. Moreover, two reaction pathways, the nucleophilic addition of water molecule across the C═O or the C═S bond of OCS are competitive.

The α-effect exhibited in gas-phase S(N)2@N and S(N)2@C reactions.

In order to explore the existence of α-effect in gas-phase S(N)2@N reactions, and to compare its similarity and difference with its counterpart in S(N)2@C reactions, we have carried out a theoretical study on the reactivity of six α-oxy-Nus (FO(-), ClO(-), BrO(-), HOO(-), HSO(-), H2NO(-)) in the S(N)2 reactions toward NR2Cl (R = H, Me) and RCl (R = Me, i-Pr) using the G2(+)M theory. An enhanced reactivity induced by the α-atom is found in all examined systems. The magnitude of the α-effect in the reactions of NR2Cl (R = H, Me) is generally smaller than that in the corresponding S(N)2 reaction, but their variation trend with the identity of α-atom is very similar. The origin of the α-effect of the S(N)2@N reactions is discussed in terms of activation strain analysis and thermodynamic analysis, indicating that the α-effect in the S(N)2@N reactions largely arises from transition state stabilization, and the "hyper-reactivity" of these α-Nus is also accompanied by an enhanced thermodynamic stability of products from the n(N) → σ*(O-Y) negative hyperconjugation. Meanwhile, it is found that the reactivity of oxy-Nus in the S(N)2 reactions toward NMe2Cl is lower than toward i-PrCl, which is different from previous experiments, that is, the S(N)2 reactions of NH2Cl is more facile than MeCl.

[Association between estrogen receptor beta gene polymorphism and intrahepatic cholestasis of pregnancy in the Uygurs and the Hans pregnant women].

OBJECTIVE: To investigate the distribution of estrogen receptor beta (ERbeta) gene polymorphisms between the Uygurs and the Hans in Urumqi and the association of the polymorphisms with intrahepatic cholestasis of pregnancy (ICP). METHODS: ICP cases and controls from a hospital were recruited from April 2008 to April 2011,and a total of 105 ICP patients in Uygurs case group and 105 ICP patients in Hans case group were randomly selected, meanwhile, 105 Uygurs and 105 Hans healthy pregnant women were recruited as control group. The distribution of Rsa I and Alu I of ERbeta gene polymorphism were analyzed by PCR amplification and restriction and other molecular biology approaches. Data were analyzed by chi2 and Fisher exact probability. RESULTS: In Uygurs case group, the genotype frequencies of rr, Rr,RR,aa, Aa and AA were 39.0% (41 cases), 50.5% (53 cases), 10.5% (11 cases), 62.7% (66 cases), 30.5% (32 cases), 6.8% (7 cases). In Uygurs control group, the frequencies were 21.0% (22 cases), 56.2% (59 cases), 22.8% (24 cases), 80.0% (84 cases), 18.1% (19 cases), 1.9% (2 cases). In Hans case group, the genotype frequencies of rr, Rr, RR, aa, Aa and AA were 40. 0% (42 cases), 45.7% (48 cases), 14.3% (15 cases), 66.7% (70 cases), 29.5% (31 cases), 3.8% (4 cases). In Hans control group,the frequencies were 29.5% (31 cases), 57.2% (60 cases), 13.3% (14 cases), 74.2% (78 cases), 23.8% (25 cases), 2.0% (2 cases). The genotype frequencies were not statistically significant between the two case groups and between the two control groups (all P values > 0.05), and between two Hans groups (P > 0.05). The frequencies of RRaa in the Uygur case group was lower(4. 76% ,5 cases)than control group (13.33%, 14 cases) (P <0.05), while the frequencies of rrAa in the Uygur case group was significantly higher (14. 29% ,15 cases)than control group (2.86%, 3 cases) (all P values < 0.05). CONCLUSION: The distribution of ERbeta gene polymorphism is of no significant difference between the Uygurs and Hans, ERbeta gene polymorphism may correlate with pathogenesis of ICP in the Uygurs other than in the Hans, and rrAa might be risk factor for ICP in the Uygurs.