Zhao-Qian Liu

Gly389Arg polymorphism of β1‐adrenergic receptor is associated with the cardiovascular response to metoprolol

Our objectives were to determine whether the Gly389 polymorphism of the β1‐adrenergic receptor exhibits reduced responsiveness in vivo and to test the hypothesis that the Gly389Arg polymorphism affects the blood pressure and heart rate response to metoprolol.

Β1-Adrenergic receptor polymorphisms influence the response to metoprolol monotherapy in patients with essential hypertension

The human β1‐adrenergic receptor, an important therapeutic target in cardiovascular diseases, has 2 common functional polymorphisms (Ser49Gly and Gly389Arg). Our study aimed to confirm that β1‐adrenergic receptor polymorphisms affect the blood pressure response to metoprolol monotherapy in the Chinese population with hypertension.

Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19

Our objective was to evaluate the relationship between the disposition of sertraline and the presence of the CYP2C19 gene and to define the contribution of cytochrome P450 2C19 (CYP2C19) to sertraline N‐demethylation.

Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation.

1 The calcineurin inhibitor cyclosporine is widely used to prevent allograft rejection after solid organ transplantation. It has a narrow therapeutic index and shows considerable interindividual differences in its pharmacokinetics. Interindividual differences in the activity and expression of the metabolising enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug efflux pump P‐glycoprotein (P‐gp) contribute considerably to cyclosporine pharmacokinetics. Variability in the activity of CYP3A4, CYP3A5 and P‐gp could be considered to result from genetic polymorphisms encoding their genes. 2 The aim of the present study was to evaluate retrospectively the effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine dose adjusted trough blood concentration during the early period after renal transplantation in Chinese patients. 3 One hundred and six renal transplant recipients in China were genotyped by polymerase chain reaction–restriction fragment length polymorphism for CYP3A4*18A, CYP3A5*3 and MDR1 C3435T. Cyclosporine whole blood levels were measured by fluorescence polarization immunoassay. Dose‐adjusted trough blood concentrations (C0) were determined and compared among the different genotype groups. 4 The frequency of the CYP3A4*18A, CYP3A5*3 and MDR1 C3435T variant alleles were 0.005 (95% confidence interval (CI) 0.048, 0.0049), 0.783 (95% CI 0.781, 0.785) and 0.528 (95% CI 0.526, 0.531), respectively, and these alleles exhibited incomplete linkage disequilibrium. The median cyclosporine dose‐adjusted C0 in CYP3A5*1/*1 genotype subjects (n = 6) was 14.8 ng/mL per mg per kg (range 11.1–26.8 ng/mL per mg per kg), in CYP3A5*1/*3 patients (n = 34) it was 23.7 ng/mL per mg per kg (range 9.0–61.0 ng/mL per mg per kg) and for CYP3A5*3/*3 patients (n = 66) it was 26.4 ng/mL per mg per kg (range 9.8–85.8 ng/mL per mg per kg; P = 0.012, Kruskal–Wallis test). Accordingly, cyclosporine dose‐adjusted C0 was larger in CYP3A5 non‐expressors than expressors in the first week after renal transplantation. In addition, wild‐type homozygotes (n = 21) for MDR1 C3435T had a slight but significantly lower dose‐adjusted C0 compared with heterozygotes (n = 58): 17.7 (10.3–60.8) versus 26.4 (9.0–67.3) ng/mL per mg per kg, respectively (P = 0.014, Mann–Whitney U‐test). 5 In conclusion, the present study shows that genetic polymorphisms in CYP3A5 may be responsible, in part, for the large interindividual variability of cyclosporine pharmacokinetics during the early phase after renal transplantation in Chinese patients. Patients with the CYP3A5*3 variant genotype require a low dose of cyclosporine to reach target levels compared with those with the CYP3A5*1 allele.

Preparative isolation and purification of seven main antioxidants from Eucommia ulmoides Oliv. (Du-zhong) leaves using HSCCC guided by DPPH-HPLC experiment

Seven antioxidants were purified from Eucommia ulmoides Oliv. leaves using HSCCC guided by DPPH-HPLC experiment. HSCCC was successfully used to separate target antioxidants by three runs with different solvent systems after D101 column chromatography fractionation. Ethyl acetate-n-butanol-water (1:2:3, v/v/v) was selected as the optimum solvent system to purify geniposidic acid. Ethyl acetate-ethanol-water (4:1:5, v/v/v) was used to isolate caffeic acid, chlorogenic acid and ferulic acid. While three flavonoids, quercetin-3-O-sambubioside, rutin and isoquercitrin were purified by petroleum ether-ethyl acetate-methanol-water (1:5:1:5, v/v/v/v). The structures were identified by MS and NMR. Antioxidant activities were assessed, and compounds 2-7 showed strong antioxidant activities. This is the first report about separation of antioxidants from E. ulmoides leaves by HSCCC. The results indicated that the combinative methods using DPPH-HPLC and HSCCC could be widely applied for screening and isolation of antioxidants from complex extracts.

OATP1B1 POLYMORPHISM IS A MAJOR DETERMINANT OF SERUM BILIRUBIN LEVEL BUT NOT ASSOCIATED WITH RIFAMPICIN-MEDIATED BILIRUBIN ELEVATION

1 Elevated serum bilirubin levels are caused mainly by liver diseases, haematolysis, genetic defects and drug intake. Unconjugated bilirubin (UCB) is taken up into hepatocytes by human organic anion transporting polypeptide 1B1 (OATP1B1; encoded for by the SLCO1B1 gene). The present study was performed to determine the association between SLCO1B1 gene polymorphisms and serum bilirubin levels in vivo. Moreover, the effects of administration of low‐dose rifampicin on serum bilirubin levels in different SLCO1B1 genotypes was examined. 2 Serum bilirubin levels were examined in 42 healthy volunteers who had been analysed for SLCO1B1 genotype (seven, 13, 14 and eight with SLCO1B1 genotypes *1a/*1a, *1b/*1b, *1b/*15 and *15/*15, respectively). Among them, 24 subjects (seven, seven, eight and two with SLCO1B1 genotypes *1a/*1a, *1b/*1b, *1b/*15 and *15/*15, respectively) were selected to participate in an open‐label, two‐phase clinical trial. Each was given 450 mg rifampicin orally once daily at 2000 hours for 5 consecutive days. Serum bilirubin concentrations at 0800 hours on the 1st and 6th days were compared between the different SLCO1B1 genotypes. 3 In the 42 volunteers, the mean (±SD) serum UCB in both SLCO1B1*1b/*15 and *15/*15 groups was significantly higher than that in the SLCO1B1*1b/*1b group (11.07 ± 2.31, 13.01 ± 3.87 and 8.21 ± 2.68 µmol/L, respectively; P = 0.009 and P < 0.001). Total bilirum (T.BIL) in both the SLCO1B1*1b/*15 and *15/*15 groups was significantly higher than that in the SLCO1B1*1b/*1b group (16.69 ± 4.09, 20.71 ± 5.12 and 13.06 ± 5.12 µmol/L, respectively; P = 0.029 and P < 0.001). The direct bilirubin (D.BIL) in the SLCO1B1*15/*15 group was significantly higher than that in the SLCO1B1*1b/*1b group (7.69 ± 1.81 vs 4.85 ± 1.81 µmol/L, respectively; P = 0.001). Rifampicin significantly increased UCB, T.BIL and D.BIL concentrations in 24 healthy volunteers (17.68 ± 5.96 vs 13.95 ± 4.44 µmol/L (P = 0.040), 5.72 ± 2.01 vs 4.35 ± 1.50 µmol/L (P = 0.028) and 12.00 ± 4.26 vs 9.61 ± 3.15 µmol/L (P = 0.035), respectively). However, the extent of the increase in serum bilirubin caused by 450 mg rifampicin for 5 days was not affected by SLCO1B1 genotype. 4 Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the serum bilirubin level. SLCO1B1*15 carriers had higher baseline serum UCB, T.BIL and D.BIL levels compared with subjects with the SLCO1B1*1a/*1a and SLCO1B1*1b/*1b genotypes. SLCO1B1*15/*15 homozygotes are more susceptible to hyperbilirubinaemia. Serum bilirubin levels could be increased by low‐dose rifampicin administration, but the extent of the increase was not associated with SLCO1B1 genotype.

The association of adiponectin allele 45T/G and −11377C/G polymorphisms with Type 2 diabetes and rosiglitazone response in Chinese patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Rosiglitazone is able to increase serum adiponectin levels significantly in Type 2 diabetic patients. :The role of genetic factors that determine the marked interindividual variability in glucose-lowering efficacy of rosiglitazone in Chinese patients is not known. The current study was designed to evaluate the impact of the adiponectin common allele 45T/G and -11377C/G polymorphisms on the response to rosiglitazone monotherapy in Chinese patients with Type 2 diabetes (T2D). WHAT THIS STUDY ADDS The genetic polymorphisms of adiponectin alleles 45T/G and -11377C/G as well as their common diplotypes are significantly associated with an attenuated fasting plasma glucose, postprandial plasma glucose and homeostasis model assessment for insulin resistance as well as an enhanced adiponectin concentration in Chinese patients with T2D after rosiglitazone treatment. AIMS The aim of the present study was to evaluate the impact of adiponectin allele T45G and C-11377G genetic polymorphisms on efficacy of rosiglitazone in Chinese patients with type 2 diabetes (T2D). METHODS Patients with T2D (n = 255) and 120 healthy volunteers were enrolled to identify 45T/G and -11377C/G genotypes by polymerase chain reaction-restriction fragment length polymorphism assay. Forty-two T2D patients with different 45T/G or -11377C/G genotypes received orally rosiglitazone as a single-dose therapy (4 mg day-1 p.o.) for 12 weeks. Serum triglyceride, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin, fasting serum insulin, postprandial serum insulin, total cholesterol, homeostasis model assessment for insulin resistance (HOMA-IR), low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol (HDL-c) and adiponectin concentration were determined before and after rosiglitazone treatment. RESULTS We showed an attenuated rosiglitazone effect in patients with -11377CG+GG heterozygote genotype on FPG, PPG, HOMA-IR compared with -11377CC homozygote genotype. However, we found an enhanced rosiglitazone effect on serum adiponectin concentration in patients with -11377CC homozygote genotype compared with -11377CG+GG heterozygote genotype (P = 0.000) and in patients with 45TG + GG heterozygote genotype compared with 45TT homozygote genotype (P = 0.018). Finally, our results showed that there was an enhanced effect in patients with -11377/45 CGTT diplotype compared with other discovered diplotypes on FPG (P = 0.001) and PPG (P = 0.003) after rosiglitazone treatment. CONCLUSIONS These data suggest that the adiponectin allele 45T/G and -11377C/G polymorphisms are significantly associated with the therapeutic efficacy of multiple-dose rosiglitazone in Chinese patients with T2D.

ABCC2 polymorphisms and haplotype are associated with drug resistance in Chinese epileptic patients.

Aims: Some study found that ATP‐binding cassette (ABC) efflux transporters play an important role in antiepileptic drug resistance, especially ABCB1 and ABCC2. The aims of this study were to evaluate the relationship between the genetic polymorphisms of ABCC2 and ABCB1 and the therapeutic efficacy of antiepileptic drugs (AEDs) in Chinese epileptic patients. Methods:ABCB1 rs1045642 (3435C>T) and ABCC2 rs717620 (−24C>T), rs3740066 (3972C>T), and rs2273697 (1249G>A) polymorphisms loci in 537 Chinese epilepsy patients (217 drug resistant patients and 320 drug responders) were genotyped by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP). Results:ABCC2 rs717620 −24TT genotype was significantly associated with drug resistant epilepsy (odds ratio [OR]= 4.06 [1.79–9.20], P= 0.001). The OR values of ABCC2 rs717620 −24 CT+TT genotypes and ABCC2 rs3740066 (3972C>T) CT+TT genotypes were markedly higher in drug resistant patients (OR = 1.57 [1.08–2.29], P= 0.018; OR = 1.49 [1.02–2.18], P= 0.038, respectively) compared with responsive patients. ABCC2 rs2273697 (1249G>A) and ABCB1 rs1045642 (3435C>T) polymorphisms were not associated with drug resistant epilepsy. Linkage disequilibrium (LD) test showed that the ABCC2 rs717620 were in strong LD with rs2273697 (D’= 0.694) and rs3740066 (D’= 0.699). The frequencies of haplotypes TGT (ABCC2 −24C>T/ABCC2 1249G>A/ABCC2 3972C>T) in resistant patients was significantly higher than those in responsive patients (21.0% vs. 14.2%, P < 0.05). Conclusion:ABCC2−24C>T, 3972C>T polymorphisms and one ABCC2 haplotype is associated with AED resistance; ABCC2 1249G>A and ABCB1 3435C>T polymorphisms are not associated with AED resistance in our study. These data suggest that ABCC2 polymorphisms and haplotype may affect the response of antiepileptic drugs.

Huperzine A Ameliorates Cognitive Deficits in Streptozotocin-Induced Diabetic Rats

The present study was designed to probe the effects of Huperzine A (HupA) on diabetes-associated cognitive decline (DACD) using a streptozotocin (STZ)-injected rat model. Diabetic rats were treated with HupA (0.05 and 0.1 mg/kg) for seven weeks. Memory functions were evaluated by the water maze test. Nissl staining was selected for detecting neuronal loss. Protein and mRNA levels of brain-derived neurotrophic factor (BDNF) were analyzed by ELISA and real-time PCR, respectively. The activities of choline acetylase (ChAT), Acetylcholinesterase (AChE), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), NF-κB p65 unit, TNF-α, IL-1β, IL-6 and caspase-3 were measured using corresponding kits. After seven weeks, diabetic rats exhibited remarkable reductions in: body weight, percentage of time spent in target quadrant, number of times crossing the platform, ChAT and BDNF levels, SOD, GSH-Px and CAT accompanied with increases in neuronal damage, plasma glucose levels, escape latency, mean path length, AChE, MDA level as well as CAT, NF-κB p65 unit, TNF-α, IL-1β, IL-6 and caspase-3 in cerebral cortex and hippocampus. Supplementation with HupA significantly and dose-dependently reversed the corresponding values in diabetes. It is concluded that HupA ameliorates DACD via modulating BDNF, oxidative stress, inflammation and apoptosis.

Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients

BACKGROUND Cisplatin toxicity severely obstacles successful chemotherapy in lung cancer patients. Cisplatin uptake is considered as one of the major factors contributing to the side effects of cisplatin. Genetic variances of core genes also affect cisplatin toxicity. It has been identified that CTR1, copper transporter protein 1, plays an essential role in cisplatin uptake. The purpose of this study is to investigate whether CTR1 polymorphism is associated with platinum toxicity in non-small cell lung cancer (NSCLC) patients. METHOD 204 incident NSCLC patients from three different institutions were enrolled and followed up. These patients were histologically confirmed with non-small cell lung cancer. All patients have accepted cisplatin-based chemotherapy for at least two cycles. Twenty SNPs of CTR1 were detected in these patients. RESULT CTR1 rs10981694 A>C polymorphism is associated with cisplatin induced severe toxicity in NSCLC patients. C-carrier subjects presented poorer tolerance to ototoxicity (p<0.05). The survival times of patients with different rs10981694 genetic polymorphism were not significantly different. CONCLUSION NSCLC patients carrying C allele of CTR1 rs10981694 presented more sensitivity to ototoxicity after cisplatin treatment. CTR1 plays an essential role in cisplatin toxicity and could be considered as a predictor for pretreatment evaluation in lung cancer patients.