Mediation of cadmium‐induced oxidative damage and glucose‐6‐phosphate dehydrogenase expression through glutathione depletion

Abstract

The effect of cadmium (Cd), a significant environmental contaminant, on the expression of glucose-6-phosphate dehydrogenase (G6PDH), has been investigated. G6PDH is the key rate-limiting enzyme in the pentose pathway and the expression of its gene has been shown to be redox-sensitive. We show that incubation of primary rat hepatocytes with Cd induces oxidative stress in a time- and concentration-dependent manner as measured by increases in the cytotoxic parameters, lactate dehydrogenase (LDH) and lipid peroxidation (LPO). Significant increases in LDH leakage and LPO can be measured after 12 and 24 h, respectively, in the presence of 4 microM cadmium chloride. However, prior to significant increases in cytotoxic parameters, and within only 6 h of Cd treatment, significant decreases in reduced glutathione and increases in the expression of G6PDH as measured by mRNA levels and enzyme activity are observed. The signal protein MAP kinase (MAPK) is also induced by Cd within 6 h. Blocking the Cd induction of MAPK using the antioxidant N-acetyl cysteine (10 mM) or Trolox (0.5 mM) or the MEK specific inhibitor PD098059 (20 microM) also blocks the Cd induction of G6PDH suggesting that MAPK is a signal protein involved in the redox regulation of this gene.

COX-2 is associated with cadmium-induced ICAM-1 expression in cerebrovascular endothelial cells

“…There is growing evidence that Cd up-regulates redox-sensitive signaling pathways such as MAPKs leading to increased expression of various genes (Xu et al, 2003;Rockwell et al, 2004). We also found that 2 M Cd increased phosphorylation of p38 MAPK, and a specific inhibitor of p38 MAPK, SB203580, blocked Cdinduced COX-2 expression and PGE 2 synthesis.…”

“…Similarly, both p38 MAPK and JNK were activated but only p38 MAPK was responsible for COX-2 expression in mouse hippocampal cells exposed to Cd (Rockwell et al, 2004). In contrast, ERK pathway is known to be involved in Cd induction of G6PDH in rat hepatocytes (Xu et al, 2003). Thus, together with our finding, these results suggest that there are differences in cell type and species specificity in relation to activation of MAPKs and types of MAPKs involved in the induction of specific genes following Cd exposure.…”

“…It has been suggested that Cd-induced ROS production might result from a disruption in mitochondrial electron transport and/or uncoupling (Pourahmad and O'Brien, 2000). Cd exposure is also known to cause disturbances in the antioxidant defense system (Ramirez and Gimenez, 2003;Xu et al, 2003). Consequently, Cd induces an imbalance in the cellular redox state, which is believed to be associated with DNA damage, altered calcium homeostasis and derangement of cellular signaling pathways (Ramirez and Gimenez, 2003).…”

Mitochondrial NADP+-Dependent Isocitrate Dehydrogenase Protects Cadmium-Induced Apoptosis

“…It has been shown that a lower concentration of Cd 2ϩ treatment increases the expression of G6PDH as measured by mRNA levels and enzyme activity in rat hepatocytes (Xu et al, 2003). Furthermore, it has been demonstrated that G6PDH activity in the ovary extract was not diminished with 1 mM Cd 2ϩ (Carattino et al, 2004).…”

Arachidonic Acid Inhibits the Insulin Induction of Glucose-6-phosphate Dehydrogenase via p38 MAP Kinase

“…Although these will not completely eliminate oxidation, peroxidation is not detectable using a thiobarbituric acid assay (6). More importantly, enhanced oxidation induces G6PD expression (39,40). Thus, if arachidonic acid was causing oxidative stress, an increase in G6PD expression would have been observed.…”