Objective. This study was conducted to investigate the thiopurine S-methyltransferase (TPMT) activity distribution and gene mutations in Kazaks, and compared the results with those of other ethnic groups. Methods. Erythrocyte TPMT activity was measured in Kazaks (n=327) via a validated highperformance liquid chromatography assay. Polymerase chain reaction-based methods were used to analyze three commonly reporter-inactivating mutations: G238C, G460A, and A719G. Results. Unimodal distribution of TPMT activity was found in Kazaks. Six TPMT*3C heterozygotes and two TPMT*3A heterozygotes were found in 327 Kazaks, with allele frequencies of 0.9 and 0.3%, respectively. The subjects with TPMT*3A and TPMT*3C heterogygotes had substantial TPMT activity over the range of 6.40Y11.75 U/ml RBC. Conclusion. Unlike in most Caucasians, TPMT*3C is a common mutant allele in Kazaks, whereas TPMT*3A is a rare mutant allele. Further studies are needed to explore the clinical impact of these TPMT mutants to thiopurine therapy in Kazak patients.

Background: Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. Several mutations in the TPMT gene have been identified which correlate with a low activity phenotype. The molecular basis for TPMT deficiency is not well defined in minority Chinese. We investigated differences in the activity of TPMT and the frequencies of mutant TPMT alleles in 4 ethnic groups of Chinese. Method: The frequency of 4 common TPMT mutant alleles, TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C, were determined in healthy subjects from Han (n =312), Jing (n=103), Yao (n=126) and Uygur Chinese (n=160) by allele-specific PCR and PCR-restriction RFLP analysis. TPMT activity in erythrocytes was determined by HPLC. Results: There was no significant difference in the mean TPMT activity between all ethnic groups studied and no subject with TPMT deficiency was found in all populations studied. TPMT*3C was found in 2.2% of Han and 1.9% of Jing Chinese. TPMT*2, TPMT*3B and TPMT*3A alleles were not detected in any of the Han or Jing Chinese tested. In contrast, 3.7% of Uygur Chinese had TPMT*3C and TPMT*3A alleles. Neither allele was detected in Yao Chinese. The overall frequencies of variant TPMT allele in Uygur were higher than in Han or Jing Chinese. However, neither the overall frequency of mutant TPMT alleles nor the genotype frequencies were significantly different between Han, Jing, Yao and Uygur Chinese. Conclusions: The TPMT*3C was the most prevalent allele in Han, Jing and Uygur Chinese, while TPMT*3A is a rare allele in Uygur Chinese who belong to Caucasian. Ethnicity may be an important factor affecting the variability in response to thiopurine chemotherapy.

Micromolar concentrations of estradiol are required to inhibit the oxidation of low-density lipoproteins (LDL) in vitro. Recent evidence suggests that estradiol must be modified before it can become an effective antioxidant at physiological levels. Our aim was to determine other possible conditions under which low concentrations of 17b-estradiol can reduce LDL oxidation. LDL susceptibility to oxidation was monitored by measurements of conjugated diene formation. High levels of 17b-estradiol reduced oxidative modification of LDL. Vitamin C and vitamin E also increased LDL resistance to Cu21-mediated oxidation. More importantly, 10 nM 17b-estradiol, which on its own had no effect, exhibited significant antioxidant actions in the presence of either vitamins C or E. In conclusion, supraphysiological concentrations of 17b-estradiol are required to exert antioxidant effects directly in vitro. However, in the presence of vitamins C and E, concentrations of 17b-estradiol close to physiological levels can also protect LDL from oxidation.

Background: The glutathione S-transferase (GST) superfamily comprises multiple isozymes with compelling evidence of functional polymorphisms in various ethnic groups. All these mutations, in particular those in class A, k and u GST, are likely to contribute to interindividual differences in responses to xenobiotics including response to chemotherapy and associated with altered disease. The frequency of common GST mutations in Uygur Chinese is unknown. We investigated the common mutations of GSTM1, GSTT1, and GSTP1 in Uygur (N =154) Chinese and compare with Han Chinese (N =196). Method: GSTM1 and GSTT1 polymorphisms were analyzed by multiplexed PCR, and GSTP1 polymorphism was detected by PCR-based restriction fragment length polymorphism (RFLP) analysis. Results: GSTM1 null genotype was found in 53.2% Uygur Chinese, which was close to that in Han Chinese (56.1%) ( P=0.592). A significantly lower frequency ( P <0.05) of GSTT1 null genotype in Uygur Chinese (26.6%) was observed compared with Han Chinese (50.0%). Uygur Chinese exhibited a GSTP1 genotype distribution of 51.3% I/I, 40.2% I/V and 8.4% V/V, which was different from that in Han Chinese (60.7% I/I, 35.2% I/V and 4.1% V/V). Conclusions: There is marked ethnic difference in the frequency of common GSTT1 and GSTP1 mutation, but not GSTM1 mutation, between Uygur and Han Chinese. D 2005 Elsevier B.V. All rights reserved.

In vitro and in vivo studies have indicated that the induction or inhibition of cytochrome P450 (CYP) is one of the major mechanisms for some clinically important pharmacokinetic herb-drug interactions. An attempt was made to simulate the effects of herbal preparation with single or multiple CYP-inhibiting constituents on the area of the plasma concentration-time curve (AUC) of coadministered drug that was either a low clearance drug by intravenous (i.v.) injection or a high clearance drug by oral route. Our simulation studies indicated that the expected increase (Rc) in the AUC of the coadministered drug by inhibiting herbal constituent(s) was dependent on the route of administration. For low clearance drug by i.v. injection, Rc was generally determined by inhibition constant (Ki), unbound inhibitor concentration ([I]), hepatic fraction (fh), number of inhibitory herbal constituents (n) and metabolic pathway fraction in hepatic metabolism (fm), while Rc for a high clearance drug by oral route, Rc was determined by Ki, [I], n and fm. By varying these parameters, Rc changed accordingly. It appeared likely to predict a herb-drug metabolic interaction, if the inhibiting herbal constituents could be quantitatively determined. However, many herb- and drug-related factors may cause difficulties with the prediction, and thus in vivo animal and human studies are always necessary. Copyright