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Aims: To examine the additive effect of the z-4 microsatellite polymorphism of aldose reductase gene (ALR2) and glycaemic control on risk of cataract in a prospective cohort of Chinese type 2 diabetic patients., Methods: The (CA)n microsatellite polymorphism of ALR2 was determined using PCR followed by capillary gel electrophoresis. Cataract was defined by presence of lens opacity on direct ophthalmoscopy or history of cataract surgery. A non-linear curve approach was used to identify the threshold of glycated hemoglobin (HbA1c) at which the odds ratio (OR) for cataract started to increase. The association of z-4 allele with cataract, above and below this threshold, was assessed using multiple logistic regression analysis., Results: Of the 5823 patients analyzed, 28.1% had cataracts. After adjusting for conventional risk factors and using non-z-4 carriers with HbA1c<8.0% as referent group (n = 3173), the OR (95% confidence intervals) for cataract was highest in z-4 carriers with HbA1c ≥ 8.0% [1.43 (1.05-1.96), n = 244], compared to non-z-4 carriers with HbA1c ≥ 8.0 [1.27 (1.10-1.47), n = 1836] and z-4 carriers with HbA1c<8.0%[1.01 (0.77-1.29), n = 420, P(trend) < 0.001]. This additive association remained significant after additional adjustments for drug use (P(trend) = 0.002) and renal function (P(trend) = 0.01)., Conclusions: In type 2 diabetic patients with suboptimal glycaemic control, the z-4 allele of ALR2 (CA)n polymorphism was independently associated with increased susceptibility to cataracts., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Diabetes is associated with an increased risk of cancer. This study aimed to evaluate associations between recently reported type 2 diabetes (T2D) susceptibility genetic variants and cancer risk in a prospective cohort of Chinese patients with T2D., Methods: Seven single nucleotide polymorphisms (SNP) in IGF2BP2, CDKAL1, SLC30A8, CDKN2A/B, HHEX and TCF7L2, all identified from genome-wide association studies of T2D, were genotyped in 5900 T2D patients [age mean ± SD = 57 ± 13 years, % males = 46] without any known cancer at baseline. Associations between new-onset of cancer and SNPs were tested by Cox proportional hazard models with adjustment of conventional risk factors., Results: During the mean follow-up period of 8.5 ± 3.3 years, 429 patients (7.3%) developed cancer. Of the T2D-related SNPs, the G-alleles of HHEX rs7923837 (hazard ratio [HR] (95% C.I.) = 1.34 (1.08-1.65); P = 6.7 ×10(-3) under dominant model) and TCF7L2 rs290481 (HR (95% C.I.) = 1.16 (1.01-1.33); P = 0.040 under additive model) were positively associated with cancer risk, while the G-allele of CDKAL1 rs7756992 was inversely associated (HR (95% C.I.) = 0.80 (0.65-1.00); P = 0.048 under recessive model). The risk alleles of these significant SNPs exhibited combined effect on increasing cancer risk (per-allele HR (95% C.I.) = 1.25 (1.12-1.39); P = 4.8 × 10(-5)). The adjusted cancer risk was 2.41 (95% C.I. 1.23-4.69) for patients with four risk alleles comparing to patients without risk allele., Conclusions: T2D-related variants HHEX rs7923837, TCF7L2 rs290481 and CDKAL1 rs7756992 increased cancer risk in patients with diabetes., Impact: Our findings provide novel insights into the pathogenesis of cancer in diabetes., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Aims/hypothesis: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians., Methods: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations., Results: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6 × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians., Conclusions/interpretation: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Medicinal mushrooms have been traditionally used as food nutrient supplements in China for thousands of years. The present study aimed to evaluate the immunomodulatory activities of Ganoderma sinense (GS), an allied species of G. lucidum, using human peripheral blood mononuclear cells (PBMC). Our results showed that the polysaccharide-enriched fraction of GS hot water extract (400 μg/ml) exhibited significant stimulatory effects on PBMC proliferation. When the fruiting bodies of GS were divided into pileus and stipe parts and were separately extracted, the GS stipe polysaccharide-enriched fraction (50-400 μg/ml) showed concentration-dependent immunostimulating effects in PBMC. The productions of tumor necrosis factor-α, interleukin (IL)-10, and transforming growth factor -β were significantly enhanced by this fraction. In addition, the proportion of CD14(+) monocyte subpopulation within the PBMC was specifically increased. The IL-10 and IL-12 productions in monocyte-derived dendritic cells were significantly enhanced by GS stipe fraction. The composition of monosaccharides of this fraction was determined by ultra performance liquid chromatography and ion exchange chromatography. Our study demonstrated for the first time the immunostimulatory effects of GS stipe polysaccharide-enriched fraction on PBMC and dendritic cells. The findings revealed the potential use of GS (especially including the stipes of fruiting bodies) as adjuvant nutrient supplements for patients, who are receiving immunosuppressive chemotherapies.

Aims/hypothesis: There is evidence of overlap between susceptibility loci for type 2 diabetes and obesity. The aim of this study is to explore the association between the established type 2 diabetes locus KCNQ1 and obesity in Han Chinese., Methods: We recruited 6,667 and 6,606 diabetic case-control samples from Shanghai and Hong Kong, respectively. Of the samples, 7.5% and 6.3% were excluded because of genotyping failure or data missing in the association analyses of rs2237892 and rs2237895 with obesity/BMI, respectively., Results: We found that rs2237892 was associated with lower BMI and lower incidence of overweight/obesity in diabetic patients from Hong Kong (BMI, β = -0.0060 per diabetes risk C allele for log(10)BMI [95% CI -0.0088, -0.0032; p = 2.83 × 10(-5)]; overweight/obesity, OR 0.880 for C allele [95% CI 0.807, 0.960; p = 0.004]) and in the meta-analysis of cases from the two regions (BMI, combined β = -0.0048 per C allele for log(10)BMI [95% CI -0.0070, -0.0026; p = 2.20 × 10(-5)]; overweight/obesity, combined OR 0.890 for C allele [95% CI 0.830, 0.955; p = 0.001]). rs2237895 was also related to decreased BMI (combined β = -0.0042 per diabetes risk C allele for log(10)BMI [95% CI -0.0062, -0.0022; p = 4.30 × 10(-5)]). A significant association with waist circumference was detected for rs2237892 in the pooled analyses (β = -0.0026 per C allele for log(10)[waist circumference] [95% CI -0.0045, -0.0007; p = 0.007]). However, neither an association with the risk of being overweight or obese nor associations with quantitive traits were detected for rs2237892 or rs2237895 in controls., Conclusion: Our findings indicate that KCNQ1 is associated with obesity in Chinese patients with type 2 diabetes.

Context: Protein kinase C-beta (PKC-beta) is a cell-signaling intermediate implicated in development of diabetic complications., Objective: To examine the risk association of PKC-beta 1 gene (PRKCB1) polymorphisms and end-stage renal disease (ESRD) in an 8-year prospective cohort of Chinese patients with type 2 diabetes., Design, Setting, and Participants: We genotyped 18 common tag single-nucleotide polymorphisms (SNPs) that span the PRKCB1 gene (r(2) = 0.80) in 1172 Chinese patients (recruited 1995-1998) without renal disease at baseline. A validation cohort included an additional 1049 patients with early-onset diabetes who were free of renal disease at baseline and were recruited after 1998., Main Outcome Measures: Associations of PRKCB1 polymorphisms under additive, dominant, and recessive genetic models with new onset of ESRD (defined as estimated glomerular filtration rate <15 mL/min/1.73 m(2) or dialysis or renal-related death) were assessed by Cox proportional hazard regression, adjusted for all conventional risk factors including use of medications., Results: After a mean (SD) of 7.9 (1.9) years, 90 patients (7.7%) progressed to ESRD. Four common SNPs were associated with ESRD (P < .05). The closely linked T allele at rs3760106 and G allele rs2575390 (r(2) = 0.98) showed the strongest association with ESRD (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.31-3.87; P = .003, and HR, 2.26; 95% CI, 1.31-3.88; P = .003, respectively). Four common variants predicted ESRD in separate models. The HR for ESRD increased with increasing number of risk alleles (P < .001) in the joint effect analysis. The adjusted risk for ESRD was 6.04 (95% CI, 2.00-18.31) for patients with 4 risk alleles compared with patients with 0 or 1 risk allele. Incidence was 4.4 per 1000 person-years (95% CI, 0.5-8.2) among individuals with 0 or 1 risk allele compared with 20.0 per 1000 person-years (95% CI, 8.8-31.1) in those carrying 4 risk alleles (6.9% of the cohort). These results were validated in a separate prospective cohort of young-onset diabetic patients. Of 1049 patients in the validation cohort, 151 (14.3%) developed chronic kidney disease (CKD) during follow-up, and there were significant associations between both the T allele of rs3760106 and the G allele of rs2575390 and development of CKD (HR, 1.68; 95% CI, 1.10-2.57; P = .02, and HR, 1.62; 95% CI, 1.07-2.47; P = .02, respectively)., Conclusion: Genetic variants in the PRKCB1 gene were independently associated with development of ESRD in Chinese patients with type 2 diabetes.

Objective: Recent genome-wide association studies have identified multiple novel loci associated with obesity in Europeans. We hypothesized that these genetic variants may be associated with obesity and type 2 diabetes (T2D) in Chinese., Research Design and Methods: We examined 14 associated single-nucleotide polymorphisms at 12 loci (NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15) in 605 healthy adults, 1087 healthy adolescents and 6013 T2D patients from Hong Kong., Results: The European at-risk alleles at five loci including GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 were significantly associated with increased body mass index (BMI), waist circumference (4.5 x 10(-8) < P < 0.024), and/or obesity risk (odds ratio 1.14-1.22, 2.0 x 10(-5) < P < 0.002) in our Chinese populations. The former four loci as well as LIN7C/BDNF were also modestly associated with T2D risk (odds ratio 1.09-1.22, 0.008 < P < 0.041), but the associations were lost after adjustment for BMI, suggesting their roles in T2D risk are mediated through modulation of adiposity. Joint effect analyses of the five adiposity loci revealed an increase of about 0.29 kg/m(2) in BMI with each additional copy of at-risk allele (P(trend) = 4.2 x 10(-12))., Conclusions: Our findings support the important contribution of GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 in the regulation of adiposity, which in turn affects T2D risk in Chinese.

Aims/hypothesis: Chromosome 1q21-q24 has been shown to be linked to type 2 diabetes. The International Type 2 Diabetes 1q Consortium showed that one of the nominal associations was located in the NOS1AP gene. Although this association was not replicated in additional samples of European descent, it remains unknown whether NOS1AP plays a role in Chinese individuals., Methods: In stage 1 analyses, 79 single nucleotide polymorphisms (SNPs) of the NOS1AP gene were successfully genotyped in a group of Shanghai Chinese individuals, comprising 1,691 type 2 diabetes patients and 1,720 control participants. In stage 2 analyses, the SNP showing the strongest association was genotyped in additional Chinese individuals, including 1,663 type 2 diabetes patients and 1,408 control participants., Results: In stage 1 analyses, 20 SNPs were nominally associated with type 2 diabetes (p < 0.05), with SNP rs12742393 showing the strongest association (OR 1.24 [95% CI 1.11-1.38]; p = 0.0002, empirical p = 0.019). Haplotype analysis also confirmed the association between rs12742393 and type 2 diabetes. In stage 2 analyses, the difference in allele frequency distribution of rs12742393 did not reach statistical significance (p = 0.254). However, the meta-analysis showed a significant association between rs12742393 and type 2 diabetes with an OR of 1.17 (95% CI 1.07-1.26; p = 0.0005)., Conclusions/interpretation: Our data suggest that NOS1AP variants may not play a dominant role in susceptibility to type 2 diabetes, but a minor effect cannot be excluded.

Objective: Recent studies in European populations have reported a reciprocal association of glucokinase regulatory protein (GCKR) gene with triglyceride versus fasting plasma glucose (FPG) levels and type 2 diabetes risk. GCKR is a rate-limiting factor of glucokinase (GCK), which functions as a key glycolytic enzyme for maintaining glucose homeostasis. We examined the associations of two common genetic polymorphisms of GCKR and GCK with metabolic traits in healthy Chinese adults and adolescents., Research Design and Methods: Two single nucleotide polymorphisms (SNPs), rs780094 at GCKR and rs1799884 at GCK, were genotyped in 600 healthy adults and 986 healthy adolescents. The associations of these SNPs with metabolic traits were assessed by linear regression adjusted for age, sex, and/or BMI. We also tested for the epistasis between these two SNPs and performed a meta-analysis among European and Asian populations., Results: The T-allele of GCKR rs780094 was associated with increased triglycerides (P = 5.4 x 10(-7)), while the A-allele of GCK rs1799884 was associated with higher FPG (P = 3.1 x 10(-7)). A novel interaction effect between the two SNPs on FPG was also observed (P = 0.0025). Meta-analyses strongly supported the additive effects of the two SNPs on FPG and triglycerides, respectively. CONCLUSIONS;- In support of the intimate relationship between glucose and lipid metabolisms, GCKR and GCK genetic polymorphisms interact to increase FPG in healthy adults and adolescents. These risk alleles may contribute to increased diabetes risk in subjects who harbor other genetic or environmental/lifestyle risk factors.

Background: To examine the lipid profile in Chinese type 2 diabetic patients and their relationship with anthropometric parameters, glycaemic control and cardiovascular mortality., Methods: A consecutive cohort of 562 newly referred patients with type 2 diabetes to a hospital-based diabetes centre were examined in 1996. Subjects treated with lipid lowering drugs at the time of referral were excluded. A total of 517 subjects were followed up over a mean (+/-SD) period of 4.6 +/- 0.9 years. Glycated haemoglobin (HbA1c), fasting insulin and lipid profile and anthropometric parameters were documented at the time of recruitment. Cardiovascular mortality, mainly due to coronary heart disease and stroke, was ascertained using death registry and review of hospital case notes in 2001., Result: Of the 517 subjects (mean age of 54.0 +/- 14.0 years), 42.6% were men. In this cohort, 63.3% of subjects were either overweight (BMI > or = 23 kg/m2) or obese (BMI > or = 25 kg/m2) using Asian criteria. The mean (+/-SD) total cholesterol (TC), LDL-Cholesterol (LDL-C), HDL-Cholesterol (HDL-C) and geometric mean (x// antilog SD) of triglycerides (TG) were 5.6 +/- 1.3 mmol/L, 3.6 +/- 1.1 mmol/L, 1.3 +/- 0.3 mmol/L and 1.46x//1.90 mmol/L respectively. TC and LDL-C correlated positively with HbA1c, HDL-C negatively with BMI and WC (waist circumference), while TG positively with HbA1c, BMI, WC and HOMA (insulin resistance estimated using the homeostasis model assessment). During the 4.6 years follow-up period, there were 61 deaths giving a total mortality rate of 11.4%, of which 15 (25%) were because of cardiovascular events. Apart from age and disease duration, logarithm of TG was significantly associated with increased risk of cardiovascular mortality (p = 0.049, relative risk = 2.97, 95% CI 1.00-8.77)., Conclusions: Chinese type 2 diabetic patients had a lower prevalence of obesity, lower TG and higher HDL-C than Caucasian patients. Despite the low incidence of cardiovascular death, TG, which was closely associated with obesity indexes, was significantly associated with cardiovascular death in these patients., (Copyright 2004 John Wiley & Sons, Ltd.)

Single-nucleotide polymorphisms (SNPs) are commonly used to study genetics for common diseases and predict pharmacological response. The selection of likely informative SNPs in association studies depends on their allele frequencies and on the linkage disequilibrium (LD) between SNPs, both of which may show interethnic differences. Among three populations consisting of 207 Chinese, 858 French, and 395 Spanish, we compared the allele frequency distributions of 64 intragenic SNPs of 35 candidate genes for cardiovascular diseases. Twenty-eight of these SNPs from 12 genes were also examined for intragenic LD. About 20% of SNPs were restricted to Europeans, being monomorphic in Chinese, among them mostly nonsynonymous coding SNPs and noncoding SNPs. Only 1.6% of SNPs were specific in Chinese, commensurate with the detection of these SNPs almost exclusively in Caucasians. Similarly, these SNPs were more often rare (<0.1 minor allele frequency) in Chinese (44.3%) than in Europeans (31.1%). The variant allele frequencies and intermarker LDs in terms of D' and Delta(2) were highly correlated between French and Spanish populations (r = 0.98-0.99, p < 0.001). However, only moderate correlations of allele frequencies and D' were found between the Chinese and the European populations (r = 0.7 and 0.3, respectively) despite a high correlation of Delta(2) values (r = 0.8). These results suggest that ethnic considerations are important in the selection of SNPs for association studies of candidate genes, as this may affect the power of the study as well as the likelihood of asking relevant questions and getting medically meaningful answers.

Objective: Previous studies have reported associations between two apolipoprotein A-I (apoA-I) gene MspI polymorphisms (G-75A and C83T) and high density lipoprotein (HDL)-cholesterol and/or apoA-I levels, but have not investigated the relationship with obesity., Methods: We determined the distribution of these polymorphisms in 482 early-onset (< or = 40 years) Type 2 Chinese diabetics and 167 Chinese selected healthy controls., Results: The -75A and 83T allele frequencies were similar in the diabetic and healthy subjects. In the healthy control subjects, HDL-cholesterol levels were significantly higher in the AA homozygotes than in the GG/GA carriers (1.74 +/- 0.58 vs. 1.45 +/- 0.58 mmol/l, P<0.001). Furthermore, analyses showed a significant relationship between increasing HDL-cholesterol tertiles and the AA genotype frequency in the selected healthy subjects (3.6, 8.9 and 16.1%, P=0.026). For the C83T polymorphism, healthy male CT carriers had higher HDL-cholesterol levels than CC homozygotes (1.71 +/- 0.57 vs. 1.25 +/- 0.30 mmol/l, P=0.001), but this was not found in females. No relationship between these polymorphisms and lipid levels was found in the diabetics, who had a more adverse lipid profile than the selected controls. In the diabetics, but not the controls, in CT carriers compared to CC homozygotes there were lower levels of body mass index (BMI; 23.8 +/- 3.9 vs. 25.4 +/- 4.7 kg/m2, P=0.048) and waist-to-height ratio (0.49 +/- 0.06 vs. 0.52 +/- 0.07, P=0.023), and this relationship was supported by tertile analysis., Conclusions: The -75AA genotype was associated with higher HDL-cholesterol levels in the selected healthy, but not diabetic, subjects. The 83T allele was associated with greater indices of obesity in the diabetic patients, and with higher HDL-cholesterol in heterozygous healthy male subjects.

The prevalence of young-onset diabetes is rapidly rising in China. Young-onset diabetes is etiologically and phenotypically heterogeneous. Thirty percent to 50% of these patients have insulin secretory failure owing to autoimmune or monogenic or other yet to be identified forms of diabetes. Others have a strong family history of diabetes and exhibit features of the metabolic syndrome. Management of these young patients poses major diagnostic and therapeutic challenges, which require a multidisciplinary and holistic approach to ensure that these subjects are identified early and managed appropriately. Understanding the molecular basis of diabetes in these subjects may also eventually lead to improvement in diagnosis, classification, and treatment.

Lipoprotein lipase (LPL) plays a central role in triglyceride metabolism, and the LPL gene T495G HindIII polymorphism has been associated with variations in lipid levels and heart disease in Caucasians with the more common H+ allele being associated with adverse lipid profiles and increased risk of CHD. We investigated this polymorphism in 785 Chinese subjects with varying components of the metabolic syndrome, including 61.4% with early-onset type 2 diabetes (age at diagnosis < or = 40 years), and 167 healthy control subjects using a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) method. The allele and genotype frequencies were similar in the patients and control subjects. When grouped above or below standard cutoffs for triglyceride levels, the H+ allele was more frequent in hypertriglyceridemic than that in normotriglyceridemic subjects in the total population (81.5% v 76.1%) and early-onset type 2 diabetics (84.4% v 77.4%, both P <.05). Moreover, H+H+ carriers had significantly higher plasma triglyceride and lower high-density lipoprotein (HDL)-cholesterol levels when compared to subjects with the H- allele in the total population, and in patients with early-onset diabetics (both P <.05). In the total population and the early-onset diabetic patients, this relationship was confined to males when gender was considered. We conclude that the H+ allele of the LPL gene HindIII polymorphism is associated with higher plasma triglyceride and lower HDL-cholesterol levels in Chinese patients with early-onset diabetes., (Copyright 2003, Elsevier Science (USA). All rights reserved.)

As we enter the new millennium, Asia is being hit by an epidemic of diabetes and its related diseases. The rising prevalence of young onset diabetes which is closely associated with obesity and genetic factors as well as the increased propensity to develop kidney disease are special challenges in the management of Chinese diabetic patients. Although diabetic patients have earlier mortality and increased risks for micro and macrovascular complications, there is strong evidence that these devastating complications can be largely prevented by patient education, periodic assessments and use of appropriate therapeutic agents to optimize metabolic control and improve cardiovascular risk factors. However, a multidisciplinary approach is often required to deliver these complex disease management protocols. Hence, it is not surprising that large scale studies often revealed substandard diabetes management in both the hospital and community settings. This is often due to a combination of factors such as non-adherence to recommended guidelines both by patients and doctors as well as the 'non-urgent' and 'silent nature' of diabetes and its complications. To minimize the impacts of diabetes on quality of life, society productivity and utilization of health care resources, concerted efforts between health care professionals and public bodies are urgently needed to increase awareness, improve standards of care and develop better diagnostics and treatment modalities.

Aims: To examine the prevalence of identified MODY-related genes in Chinese subjects with early onset Type 2 diabetes mellitus and a positive family history of diabetes and to look for possible associations between the gene mutations and the development of diabetes., Methods: Ninety-two unrelated Chinese subjects with diabetes diagnosed before the age of 40 years who had a positive family history of diabetes were screened for mutations in hepatocyte nuclear factors (HNF-1alpha and HNF-4alpha) and glucokinase genes by direct sequencing. The family members of patients with mutations and 100 healthy controls were also examined., Results: Mutations in the HNF-1alpha and the glucokinase genes were found in 5% and 3% of the diabetic subjects, respectively but no mutations were found in the coding region of the HNF-4alpha gene. Three mutations found in the glucokinase gene were novel missense mutations (I110T, A119D and G385V). The mutations in the HNF-1alpha gene were also new and included four missense mutations (G20R, R203H, S432C, I618M) and one splice acceptor site mutation (IVS2nt-1G-->A). Patients with mutations in these genes were clinically heterogeneous with respect to phenotype and basal pancreatic beta cell function., Conclusions: Genetic factors such as mutations in the HNF-1alpha and glucokinase genes may be important in the development of diabetes in Chinese people, especially when the disease is of early onset.

Background: The biotransformation of xenobiotics into toxic metabolites by cytochrome P-450 has been implicated in carcinogenesis. This study investigated CYP3A4 activity, which metabolically activates procarcinogens such as aflatoxin B1, by measuring the urinary 6 beta-hydroxycortisol (6 beta OHF) to free cortisol (F) ratio in patients with hepatocellular carcinoma (HCC) and other chronic liver diseases., Methods: One hundred forty-three controls and 150 patients with different liver diseases, including chronic liver disease (due to alcoholism and/or chronic hepatitis B virus infection), cirrhosis (any cause), and resectable and nonresectable HCC, were recruited. Twenty-four hour urine samples were collected for measurement of 6 beta OHF and free cortisol by an enzyme-linked immunosorbent assay (ELISA) and a radioimmunoassay, respectively., Results: Patients with nonresectable HCC showed a significant increase in 6 beta OHF excretion as well as their 6 beta OHF/F ratio (P < 0.05) when compared with the controls and other liver disease groups including patients with resectable HCC. The nonresectable HCC group showed a bimodal distribution in the 6 beta OHF/F ratio. Using a ratio of 9 or more in all HCC patients, the sensitivity and specificity of using the 6 beta OHF/F ratio to predict nonresectability of HCC was 48.8% and 92.6%, respectively., Conclusions: Our results show an increase in mean CYP3A4 enzyme activity, reflected as an increase in the 6 beta OHF/F ratio, in Hong Kong Chinese with nonresectable HCC compared with those with resectable HCC and other liver diseases. Although the role of increased CYP3A4 activity in the aetiology of HCC is not known, our specificity and sensitivity estimates suggest that a high 6 beta OHF/F ratio indicates probable inoperability. However, a normal level is a poor predictor of resectability.

Objective: Anticonvulsant drugs are known inducers of cytochrome P450 liver enzymes and it has been suggested that this induction increases susceptibility to paracetamol-induced hepatotoxicity., Methods: We measured the percentage urinary recovery of paracetamol and its metabolites after a dose of 20 mg kg-1, and the excretion of 6 beta-hydroxycortisol as a ratio to urinary free cortisol (6 beta OHF/F) in Chinese epileptic patients maintained on long-term therapy with carbamazepine (n = 6) or phenytoin (n = 6)., Results: Compared to the healthy controls (n = 20), patients on phenytoin had significantly lower recoveries of mercapturic acid, cysteine and sulphate metabolites, but a higher recovery of glucuronide metabolites of paracetamol. The recoveries of paracetamol metabolites in patients on carbamazepine were not different from controls. In contrast, the 6 beta OHF/F was significantly higher in patients on carbamazepine (3-fold) or phenytoin (2-fold) compared to controls. Healthy control Chinese subjects metabolised paracetamol in a similar way to that reported in Caucasians, indicating that the risk for hepatotoxicity would be the same. Our findings in a group of Chinese patients on phenytoin were also similar to those previously reported in Caucasians on this drug. The apparent differences in the pattern of isoenzyme induction between the groups on phenytoin and carbamazepine require verification in larger studies. The data do not suggest an increased risk of paracetamol-induced hepatotoxicity in Chinese patients on anticonvulsants.