L-Cysteine in vitro can restore cellular glutathione and inhibits the expression of cell adhesion molecules in G6PD-deficient monocytes.

L-Cysteine is a precursor of glutathione (GSH), a potent physiological antioxidant. Excess glucose-6-phosphate dehydrogenase (G6PD) deficiency in African Americans and low levels of L-cysteine diet in Hispanics can contributes to GSH deficiency and oxidative stress. Oxidative stress and monocyte adhesion was considered to be an initial event in the progression of vascular dysfunction and atherosclerosis. However, no previous study has investigated the contribution of GSH/G6PD deficiency to the expression of monocyte adhesion molecules. Using human U937 monocytes, this study examined the effect of GSH/G6PD deficiency and L-cysteine supplementation on monocyte adhesion molecules. G6PD/GSH deficiency induced by either siRNA or inhibitors (6AN/BSO, respectively) significantly (p < 0.005) increased the levels of cell adhesion molecules (ICAM-1, VCAM-1, SELL, ITGB1 and 2); NADPH oxidase (NOX), reactive oxygen species (ROS) and MCP-1 were upregulated, and decreases in levels of GSH, and nitric oxide were observed. The expression of ICAM-1 and VCAM-1 mRNA levels increased in high glucose, MCP-1 or TNF-α-treated G6PD-deficient compared to G6PD-normal cells. L-Cysteine treatment significantly (p < 0.005) increased G6PD activity and levels of GSH, and decreased NOX, ROS, and adhesion molecules. Thus, GSH/G6PD deficiency increases susceptibility to monocyte adhesion processes, whereas L-cysteine supplementation can restore cellular GSH/G6PD and attenuates NOX activity and expression of cell adhesion molecules.

Glucose-6-Phosphate Dehydrogenase Deficiency and the Need for a Novel Treatment to Prevent Kernicterus.

Hyperbilirubinemia occurs frequently in newborns, and in severe cases can progress to kernicterus and permanent developmental disorders. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human enzymopathies, is a major risk factor for hyperbilirubinemia and greatly increases the risk of kernicterus even in the developed world. Therefore, a novel treatment for kernicterus is needed, especially for G6PD-deficient newborns. Oxidative stress is a hallmark of bilirubin toxicity in the brain. We propose that the activation of G6PD via a small molecule chaperone is a potential strategy to increase endogenous defense against bilirubin-induced oxidative stress and prevent kernicterus.

Identifying term breast-fed infants at risk of significant hyperbilirubinemia.

BACKGROUND: The aim of this study was to establish a model to identify term breast-fed infants who are at risk of developing significant neonatal hyperbilirubinemia. METHODS: A prospective study was designed to investigate the effects of birth weight, mode of delivery, cephalohematoma, glucose-6-phosphate dehydrogenase (G6PD) deficiency, predischarge total serum bilirubin, variant uridine 5'diphospho-glucuronosyltransferase 1A1 (UGT1A1) gene, and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene on significant hyperbilirubinemia in term breast-fed neonates. Significant hyperbilirubinemia was defined as a bilirubin level exceeding the hour-specific phototherapy treatment threshold recommended by the American Academy of Pediatrics in 2004. RESULTS: Of 240 exclusively breast-fed term neonates, 26 (10.8%) had significant hyperbilirubinemia. The predischarge total serum bilirubin on the third day (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.87-3.70; P < 0.001) and the variant UGT1A1 gene at nucleotide 211 (OR = 5.00; 95% CI: 1.08-23.03; P < 0.05) were significant risk factors. The area under the receiver operating characteristic (ROC) curve of the predictive probability was 0.964 (95% CI: 0.932-0.984; P < 0.0001). CONCLUSION: Combining the total serum bilirubin on the third day and the variant UGT1A1 gene at nucleotide 211 can predict hyperbilirubinemia well in term breast-fed infants.

An in vivo drug screening model using glucose-6-phosphate dehydrogenase deficient mice to predict the hemolytic toxicity of 8-aminoquinolines.

Anti-malarial 8-aminoquinolines drugs cause acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDD). Efforts to develop non-hemolytic 8-aminoquinolines have been severely limited caused by the lack of a predictive in vivo animal model of hemolytic potential that would allow screening of candidate compounds. This report describes a G6PDD mouse model with a phenotype closely resembling the G6PDD phenotype found in the African A-type G6PDD human. These G6PDD mice, given different doses of primaquine, which used as a reference hemolytic drug, display a full array of hemolytic anemia parameters, consistently and reproducibly. The hemolytic and therapeutic indexes were generated for evaluation of hemotoxicity of drugs. This model demonstrated a complete hemolytic toxicity response to another known hemolytic antimalarial drug, pamaquine, but no response to non-hemolytic drugs, chloroquine and mefloquine. These results suggest that this model is suitable for evaluation of selected 8-AQ type candidate antimalarial drugs for their hemolytic potential.

Α-lipoic acid supplementation up-regulates antioxidant capacity in adults with G6PD deficiency.

The purpose of this study was to examine the effect of α-lipoic acid (LA) supplementation on blood redox status in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Eight adults with G6PD deficiency (D group) and eight controls with normal G6PD levels (N group) participated in this study. Participants received LA (600 mg/day) for 28 days. At baseline, 2 and 4 weeks after supplementation, venous blood was collected for analysis of reduced glutathione (GSH), catalase, protein carbonyls (PC), thiobarbituric acid reactive substances (TBARS), total antioxidant capacity (TAC), bilirubin, uric acid (UA) and hemoglobin (Hb) levels. Baseline GSH was lower (P<0.05) in D compared to N group whereas LA supplementation for 2 and 4 weeks increased significantly (P<0.05) GSH levels in both groups. Catalase and TAC increased (P<0.05) in both groups following 2 and 4 weeks of supplementation. Baseline TBARS values were higher (P<0.05) in D compared to N group while LA supplementation reduced (P<0.05) TBARS and PC in both groups. There were no differences for UA at baseline between the two groups but LA supplementation increased significantly UA levels only in the D group. Bilirubin and Hb were unchanged. These results indicate that LA supplementation may modulate redox status regardless G6PD deficiency.

[Studies on influence of Siwu decoction and its composite drugs on chemical-induced blood-deficiency model mice].

OBJECTIVE: To investigate Siwu decoction and its composite drugs on the blood-deficiency model mice induced by acetylphenyhydrazine and cyclophosphamide. METHOD: Acetylphenyhydrazine and cyclophosphamide were used to copy the blood-deficiency model mice. Automatic hematology analyzer was used to test the peripheral hemogram. Weighting method was used to test the liver index and spleen index; Kits for ATPase test was used to test the activities of Na+ - K+ - ATPase/Ca2+ - Mg2+ - ATPase in erythrocyte membrane. Flow cytometry was used to test the bone marrow cells' cell cycle. RESULT: Angelicar Sinensis Radix and Paeoniae Radix Alba had the most effective activity on the peripheral hemogram. Paeoniae Radix Alba, the drug pair including Angelicar Sinensis Radix and the drug- group including Paeoniae Radix Alba had the most effective activity on the liver index. All the drugs, drug-pairs, drug-groups and the formula had effect on the spleen index. To the activity of Na+ - K+ - ATPase in erythrocyte membrane, Rehmanniae Radix Praeparata, the drug-pairs and drug-groups including Angelicar Sinensis Radix exhibited the most effective activity. All the drugs, drug-pairs, drug-groups and the formula had the protective effect on the damaged bone marrow cells. CONCLUSION: Siwu decoction and its composite drugs all had effect on the blood-deficiency model mice, but the action intensity was different. Angelicar Sinensis Radix and Paeoniae Radix Alba exhibited the most effective activity to the protection of the blood-deficiency model mice.

The effect of ascorbic acid on sodium nitrite-induced methemoglobin formation in glucose-6-phosphate dehydrogenase-deficient erythrocytes.

Ascorbic acid significantly reduced the occurrence of sodium nitrite-induced methemoglobin (METHB) formation in a dose-dependent manner in erythrocytes from glucose-6-phosphate dehydrogenase (G-6-PD)-deficient humans in vitro. The ascorbic acid treatment, however, also decreased levels of reduced GSH in a dose-dependent manner, a response indicative of oxidant stress to the erythrocyte membrane. The latter findings are inconsistent with the hypothesis that ascorbic acid supplementation in G-6-PD-deficient humans may help compensate for inherently low levels of erythrocyte GSH. Finally, the ascorbic acid-induced reduction of METHB values, while of statistical significance, does not appear to be of clinical significance.