NAD(P)H:Quinone Oxidoreductase 1 Expression in Kidney Podocytes

Abstract

(FZ,TW,JB,AM), and Institute of Pathology of Southern Switzerland, Locarno, Switzerland (EP) S U M M A R Y NAD(P)H:quinone oxidoreductase 1 (NQO1; DT-diaphorase; DTD) is a cytosolic two-electron reductase, and compounds of the quinone family such as mitomycin C are efficiently bioactivated by this enzyme. The observation that DT-diaphorase is highly expressed in many cancerous tissues compared to normal tissues has provided us with a potentially selective target that can be exploited in the design of novel anticancer agents. Because of the relative lack of information about the cell-specific expression of DT-diaphorase, the purpose of this study was to map the distribution of this enzyme in normal human tissues. Fifteen tissue samples from normal human kidney were analyzed for expression of DT-diaphorase by immunohistochemistry (two-step indirect method). We found a specific high expression of DT-diaphorase in glomerular visceral epithelial cells (podocytes). These results suggest that a high expression of DT-diaphorase in podocytes could play a major role in the pathogenesis of renal toxicity and mitomycin C-induced hemolytic uremic syndrome, in which injury to the glomerular filtration mechanism is the primary damage, leading to a cascade of deleterious events including microangiopathic hemolytic anemia and thrombocytopenia. This observation has potential therapeutic implications because the DT-diaphorase metabolic pathway is influenced by many agents, including drugs, diet, and environmental cell factors such as pH and oxygen tension.

Preclinical Evaluation of the Pharmacodynamic Properties of 2,5-Diaziridinyl-3-Hydroxymethyl-6-Methyl-1,4-Benzoquinone

“…This is consistent with the observation that RH1 is metabolized slowly in mouse kidney compared with the bioreductive drug EO9 (42). It is conceivable that this may predict low or no renal toxicity in man, despite high levels of NQO1 in kidney podocytes (22,23). Clearly, the use of cyclodextrin as a vehicle for RH1 may enhance this drugs efficacy.…”

A review on the role of quinones in renal disorders

“…The likely role is a detoxifying enzyme, protecting the kidney from chemically reactive metabolites filtered through the glomerulus. Mitomycin C is an anticancer agent that is particularly toxic to the kidney and known to cause hemolytic uremic syndrome (Zappa et al2003). It is a quinone that requires cellular reduction to activate its cytotoxic effects.…”

“…Due to its ability to reduce quinones, NQO1 in podocytes could play a major role in the pathogenesis of renal toxicity and mitomycin C-induced hemolytic uremic syndrome. Injury to the glomerular filtration mechanism is the primary damage, leading to a cascade of deleterious events including microangiopathic hemolytic anemia and thrombocytopenia (Zappa et al2003). The high expression of NQO1 explains, in theory, a selective toxicity towards podocytes.…”

EO9 (Apaziquone): from the clinic to the laboratory and back again

“…schedule (q1wk), a maximum tolerated dose of 14 mg·m −2 was reported, and the dose limiting toxicity was again reversible proteinuria (McLeod et al ., 1996; Aamdal et al ., 2000). Damage to glomeruli was observed in the clinical trial, and this correlated with high levels of NQO1 in the kidney (Segura‐Aguilar et al ., 1994; Zappa et al ., 2003). A total of three partial responses were recorded in the phase I studies: two in patients with adenocarcinoma of unknown primary site and one in a patient with bile duct cancer.…”