Byung Kook Lee

Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy.

The NAD(P)H quinone oxidoreductase (NQO1:EC 1.6.99.2) is an important biotransformation enzyme system that is also known to metabolize important novel chemotherapeutic compounds. The gene that codes for this enzyme has recently been found to be polymorphic in humans. Here, we describe the ethnic distribution of the polymorphism and note that this may have implications for anti-tumour drug development and use.

Associations of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with polymorphisms in the vitamin D receptor and [delta]-aminolevulinic acid dehydratase genes.

A cross-sectional study was performed to evaluate the influence of polymorphisms in the [delta]-aminolevulinic acid dehydratase (ALAD) and vitamin D receptor (VDR) genes on blood lead, tibia lead, and dimercaptosuccinic acid (DMSA)-chelatable lead levels in 798 lead workers and 135 controls without occupational lead exposure in the Republic of Korea. Tibia lead was assessed with a 30-min measurement by (109)Cd-induced K-shell X-ray fluorescence, and DMSA-chelatable lead was estimated as 4-hr urinary lead excretion after oral administration of 10 mg/kg DMSA. The primary goals of the analysis were to examine blood lead, tibia lead, and DMSA-chelatable lead levels by ALAD and VDR genotypes, controlling for covariates; and to evaluate whether ALAD and VDR genotype modified relations among the different lead biomarkers. There was a wide range of blood lead (4-86 microg/dL), tibia lead (-7-338 microg Pb/g bone mineral), and DMSA-chelatable lead (4.8-2,103 microg) levels among lead workers. Among lead workers, 9.9% (n = 79) were heterozygous for the ALAD(2) allele and there were no homozygotes. For VDR, 10.7% (n = 85) had the Bb genotype, and 0.5% (n = 4) had the BB genotype. Although the ALAD and VDR genes are located on different chromosomes, lead workers homozygous for the ALAD(1) allele were much less likely to have the VDR bb genotype (crude odds ratio = 0.29, 95% exact confidence interval = 0.06-0.91). In adjusted analyses, subjects with the ALAD(2) allele had higher blood lead levels (on average, 2.9 microg/dL, p = 0.07) but no difference in tibia lead levels compared with subjects without the allele. In adjusted analyses, lead workers with the VDR B allele had significantly (p < 0.05) higher blood lead levels (on average, 4.2 microg/dL), chelatable lead levels (on average, 37.3 microg), and tibia lead levels (on average, 6.4 microg/g) than did workers with the VDR bb genotype. The current data confirm past observations that the ALAD gene modifies the toxicokinetics of lead and also provides new evidence that the VDR gene does so as well.

National estimates of blood lead, cadmium, and mercury levels in the Korean general adult population

ObjectivesTo assess the extent of exposure to lead, cadmium, and mercury in the Korean general adult population using a representative sample.MethodsWe studied blood concentrations of three heavy metals in a representative sample of 1,997 Koreans as part of the Third Korean National Health and Nutrition Examination Survey (KNHANES III) performed in 2005.ResultsThe geometric means of the blood lead, cadmium, and mercury concentrations were 2.61xa0μg/dL, 1.53xa0μg/L, and 4.15xa0μg/L, respectively [95% confidence intervals (CIs), 2.50–2.71, 1.48–1.58, and 3.94–4.36, respectively]. Women had significantly lower blood lead and mercury concentrations in adjusted and unadjusted analyses but no difference between genders was observed in blood cadmium analysis. The geometric means of blood lead and mercury levels were higher in subjects older than 40xa0years than in those younger than 40xa0years. Smoking status only affected the blood lead concentration, with this being higher in smokers than in nonsmokers. Blood cadmium levels did not differ with demographic and lifestyle variables after covariate adjustment. Blood mercury concentrations were higher in those who consumed alcohol and also increased with the frequency of fish consumption.ConclusionsThis biomonitoring study of blood heavy metals in the Korean general population as part of KNHANES III provides important reference data stratified by demographic and lifestyle factors that will be useful for the ongoing surveillance of environmental exposure of the Korean general population to heavy metals.

Occupational Lead Exposure and Longitudinal Decline in Neurobehavioral Test Scores

Background: No previous longitudinal studies have compared and contrasted associations of blood lead and tibia lead with declines in cognitive function over the course of time in a large sample of subjects with current and past occupational exposure to inorganic lead. Methods: From 1997 through 2001, we conducted a longitudinal study of 803 current and former lead workers in South Korea to evaluate effects on the central and peripheral nervous systems. Three study visits occurred during a mean follow-up duration of 2.20 years. Neurobehavioral test scores, peripheral nervous system function, and blood lead were measured at each of the 3 study visits, whereas tibia lead was measured by x-ray fluorescence at the first and second visits. We limited our analysis to the 576 lead workers who completed testing at all 3 visits. We performed regression analyses using generalized estimating equations. Results: There were consistent associations of blood lead with test scores at baseline and of tibia lead with declines in test scores over the next year, mainly in executive abilities, manual dexterity, and peripheral vibration threshold. Conclusions: The results support the inference that occupational lead exposure can cause declines in cognitive function over the course of time. Lead likely has an acute effect on neurobehavioral test scores as a function of recent dose and a longer-term (possibly progressive) effect on cognitive decline as a function of cumulative dose.

Association of serum ferritin with metabolic syndrome and diabetes mellitus in the South Korean general population according to the Korean National Health and Nutrition Examination Survey 2008.

We examined the association of serum ferritin levels with metabolic syndrome (MS) and diabetes mellitus in a representative sample of the adult South Korean population using data from the 2008 Korean National Health and Nutrition Examination Survey. We conducted a cross-sectional study of 6311 adults older than 20 years who participated in the 2008 Korean National Health and Nutrition Examination Survey. Metabolic syndrome was defined as the presence of at least 3 of the following: elevated blood pressure, low high-density lipoprotein cholesterol, elevated serum triglycerides, elevated plasma glucose, and abdominal obesity. Diabetes mellitus was defined as fasting glucose of at least 126 mg/dL. Insulin resistance was determined using the homeostasis model assessment estimate of insulin resistance. In a representative sample of the adult Korean population, MS was more prevalent in the highest quartile compared with the lowest quartile of serum ferritin concentrations in women following adjustments for age, education, smoking, alcohol intake, body mass index, aspartate aminotransferase, and alanine aminotransferase. Diabetes mellitus was more prevalent in the highest quartile compared with the lowest quartile of serum ferritin concentrations in premenopausal women and men. The geometric means of fasting insulin and insulin resistance determined using the homeostasis model assessment of insulin resistance in the fourth serum ferritin quartiles of postmenopausal women and men were significantly higher compared with those in the first quartile of the respective groups. The present study demonstrates that elevated serum ferritin concentrations are associated with an increased risk of MS and diabetes mellitus in a representative sample of the adult South Korean population.

Associations of lead biomarkers with renal function in Korean lead workers

Aims: To compare associations of lead biomarkers with renal function in current and former lead workers. Methods: Cross sectional analysis of first year results from a longitudinal study of 803 lead workers and 135 controls in South Korea. Clinical renal function was assessed by blood urea nitrogen (BUN), serum creatinine, and measured and calculated creatinine clearance. Urinary N-acetyl-β-D-glucosaminidase (NAG) and retinol-binding protein were also measured. Results: Mean (SD) tibia lead, blood lead, and DMSA chelatable lead levels in lead workers were 37.2 (40.4) μg/g bone mineral, 32.0 (15.0) μg/dl, and 767.8 (862.1) μg/g creatinine, respectively. Higher lead measures were associated with worse renal function in 16/42 models. When influential outliers were removed, higher lead measures remained associated with worse renal function in nine models. An additional five associations were in the opposite direction. Effect modification by age was observed. In 3/16 models, associations between higher lead measures and worse clinical renal function in participants in the oldest age tertile were significantly different from associations in those in the youngest age tertile which were in the opposite direction. Mean urinary cadmium (CdU) was 1.1 μg/g creatinine (n = 191). Higher CdU levels were associated with higher NAG. Conclusions: These data suggest that lead has an adverse effect on renal function in the moderate dose range, particularly in older workers. Associations between higher lead measures and lower BUN and serum creatinine and higher creatinine clearances may represent lead induced hyperfiltration. Environmental cadmium may also have an adverse renal impact, at least on NAG.

delta-Aminolevulinic acid dehydratase genotype modifies four hour urinary lead excretion after oral administration of dimercaptosuccinic acid.

OBJECTIVES: Previous research suggests that binding of lead by delta-aminolevulinic acid dehydratase (ALAD) may vary by ALAD genotype. This hypothesis was tested by examining whether ALAD genotype modifies urinary lead excretion (DMSA chelatable lead) after oral administration of dimercaptosuccinic acid (DMSA). METHODS: 57 South Korean lead battery manufacturing workers were given 5 mg/kg oral DMSA and urine was collected for four hours. Male workers were randomly selected from two ALAD genotype strata (ALAD1-1, ALAD1-2) from among all current workers in the two plants (n = 290). Subjects with ALAD1-1 (n = 38) were frequency matched with subjects with ALAD1-2 (n = 19) on duration of employment in the lead industry. Blood lead, zinc protoporphyrin, and plasma aminolevulinic acid concentrations, as well as ALAD genotype, duration of exposure, current tobacco use, and weight were examined as predictors or effect modifiers of levels of DMSA chelatable lead. RESULTS: Blood lead concentrations ranged from 11 to 53 micrograms/dl, with a mean (SD) of 25.4 (10.2) micrograms/dl. After 5 mg/kg DMSA orally, the workers excreted a mean (SD) 85.4 (45.0) micrograms lead during a four hour urine collection (range 16.5-184.1 micrograms). After controlling for blood lead concentrations, duration of exposure, current tobacco use, and body weight, subjects with ALAD1-2 excreted, on average, 24 micrograms less lead during the four hour urine collection than did subjects with ALAD1-1 (P = 0.05). ALAD genotype seemed to modify the relation between plasma delta-aminolevulinic acid (ALA) and DMSA chelatable lead. Workers with ALAD1-2 excreted more lead, after being given DMSA, with increasing plasma ALA than did workers with ALAD1-1 (P value for interaction = 0.01). CONCLUSIONS: DMSA chelatable lead may partly reflect the stores of bioavailable lead, and the current data indicate that subjects with ALAD1-2 have lower stores than those with ALAD1-1. These data provide further evidence that the ALAD genotype modifies the toxicokinetics of lead-for example, by differential binding of current lead stores or by differences in long-term retention and deposition of lead.

Aminolevulinic acid dehydratase genotype mediates plasma levels of the neurotoxin, 5-aminolevulinic acid, in lead-exposed workers.

The first intermediate substrate in the heme synthetic pathway, 5-aminolevulinic acid (ALA), is neurotoxic in animal models and may be responsible for some of the adverse neurologic outcomes in lead poisoning and porphyria in adult humans. ALA is a substrate for the enzyme aminolevulinic acid dehydratase (ALAD; EC 4.2.1.24), which is encoded by the ALAD gene containing 2 co-dominant alleles, 1 and 2. We measured plasma ALA (ALAP) and urinary ALA (ALAU) in 65 Korean lead workers, of whom 44 were homozygous for ALADI (ALAD1-1 genotype) and 21 were heterozygous for ALAD (ALAD1-2 genotype). ALAP in subjects with the ALAD1-1 genotype was significantly higher than in those with the ALAD1-2 genotype (Wilcoxon rank sum test, P = 0.01). No difference between ALAD genotypes was found for age, zinc protoporphyrin (ZPP), blood lead levels (PbB), ALAU, or ALAU adjusted for creatinine. ALAP was significantly correlated with ZPP (Spearmans r = 0.38, P = 0.002) and with PbB (r = 0.34, P = 0.006), and marginally with employment duration (r = 0.22, P = 0.08). ALAP remained significantly elevated (P = 0.032) in ALAD1-1 subjects after adjustment for PbB and age by multiple linear regression. These results suggest that ALAD1-1 subjects respond differently and may be more susceptible than ALAD1-2 subjects to the ALA-mediated neurotoxic effects of lead.

Associations of blood lead, cadmium, and mercury with estimated glomerular filtration rate in the Korean general population: analysis of 2008-2010 Korean National Health and Nutrition Examination Survey data.

INTRODUCTIONnThe objective of this study was to evaluate associations between blood lead, cadmium, and mercury levels with estimated glomerular filtration rate in a general population of South Korean adults.nnnMETHODSnThis was a cross-sectional study based on data obtained in the Korean National Health and Nutrition Examination Survey (KNHANES) (2008-2010). The final analytical sample consisted of 5924 participants. Estimated glomerular filtration rate (eGFR) was calculated using the MDRD Study equation as an indicator of glomerular function.nnnRESULTSnIn multiple linear regression analysis of log2-transformed blood lead as a continuous variable on eGFR, after adjusting for covariates including cadmium and mercury, the difference in eGFR levels associated with doubling of blood lead were -2.624 mL/min per 1.73 m² (95% CI: -3.803 to -1.445). In multiple linear regression analysis using quartiles of blood lead as the independent variable, the difference in eGFR levels comparing participants in the highest versus the lowest quartiles of blood lead was -3.835 mL/min per 1.73 m² (95% CI: -5.730 to -1.939). In a multiple linear regression analysis using blood cadmium and mercury, as continuous or categorical variables, as independent variables, neither metal was a significant predictor of eGFR. Odds ratios (ORs) and 95% CI values for reduced eGFR calculated for log2-transformed blood metals and quartiles of the three metals showed similar trends after adjustment for covariates.nnnDISCUSSIONnIn this large, representative sample of South Korean adults, elevated blood lead level was consistently associated with lower eGFR levels and with the prevalence of reduced eGFR even in blood lead levels below 10 μg/dL. In conclusion, elevated blood lead level was associated with lower eGFR in a Korean general population, supporting the role of lead as a risk factor for chronic kidney disease.

Iron deficiency increases blood manganese level in the Korean general population according to KNHANES 2008.

INTRODUCTIONnWe present data from Korean National Health and Nutritional Examination Survey (KNHANES) 2008 on the distribution of blood manganese (Mn) levels and their associations with iron deficiency in a representative sample of the adult Korean population.nnnMETHODSnThis study was based on data obtained in KNHANES 2008, which was conducted for three years (2007-2009) using a rolling sampling design that involves a complex, stratified, multistage, probability-cluster survey of a representative sample of the noninstitutionalized civilian population in South Korea.nnnRESULTSnGeometric means (GMs) of blood Mn in the low serum ferritin group in women, men, and all participants were significantly higher than in the normal group. GMs of blood Mn in the low-normal serum ferritin groups in women and all participants were significantly higher than in the normal group. In addition, multiple regression analysis after controlling for covariates including gender, age, regional area, education level, and smoking and drinking status showed that blood Mn was significantly higher in the low ferritin group in women, men, and all participants compared with the normal group, whereas blood Mn was significantly higher in the low-normal ferritin group only in women and all participants.nnnDISCUSSIONnThe present study shows that iron deficiency increases blood Mn level in the general population. To the best of our knowledge, the present study is the first to show an association between blood Mn level and ferritin level in a representative sample of the adult population such as that evaluated in KNHANES.