Cytosolic NAD(P)H:(Quinone‐acceptor)oxidoreductase in human normal and tumor tissue: Effects of cigarette smoking and alcohol

Abstract

NAD(P)H:(quinone-acceptor)oxidoreductase (QAO), previously known as DT-diaphorase, catalyzes the reduction of quinones to hydroquinones. Enhanced activity of the enzyme has been suggested to protect cells against the cellular toxicity and carcinogenicity of quinones, but may activate some cytotoxic anti-tumor quinones. Cytosolic levels of QAO, carbonyl reductase (CR) and total quinone reductase activity have been measured in normal and tumorous human tissues. QAO was the major component of the total cytosolic quinone reductase activity in all the tissues investigated. CR represented 10 to 28% of the total cytosolic quinone reductase activity in normal tissue. Normal tissue QAO was high in the stomach and kidney, and lower in the lung, liver, colon and breast. Primary tumor from lung, liver, colon and breast had elevated levels of QAO compared to normal tissue, while tumor from kidney and stomach had lower levels. CR was not significantly altered in tumor tissue, except in the case of lung and colon tumor which showed an increase compared to normal tissue. A major determinant of the variability of human lung tumor QAO was the cigarette-smoking history of the donor. Non-smokers and past smokers had high levels of tumor QAO compared to normal tissue. Smokers had levels of tumor QAO that were not significantly different from those of normal tissue QAO. Smokers had a small increase in normal lung QAO compared to non-smokers. Alcohol use was associated with an increase in lung tumor QAO but had no effect on QAO in normal lung. The function of QAO in tumors is not known but the elevated activity of QAO in some tumors and the apparent depressant effect of smoking could influence the response of these tumors to quinone drugs or toxic agents that are metabolized by QAO.

Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents

“…Several DT-diaphorases have been identified in humans (Jaiswal et al, 1990;Jaiswal, 1991), but the NQO, gene has been most extensively studied and appears to be most important for activation of bioreductive anti-tumour agents (Jaiswal, 1991;Riley and Workman, 1992;Belinsky and Jaiswal, 1993). Enzyme levels have been shown to be relatively high in mouse and/or human stomach, bladder, intestine, colon and kidney, but are usually low in liver, lung and haematopoietic cells (Benson et al, 1980;Schlager and Powis, 1990;Smitskamp-Wilms et al, 1995). DT-diaphorase activity is higher in some tumour cells than in the corresponding normal cells, with elevated levels of enzyme activity having been observed in human liver, colon, breast and lung tumour cells (Schlager and Powis, 1990;Malkinson et al, 1992;Belinsky and Jaiswal, 1993;Smitskamp-Wilms et al, 1995).…”

“…Enzyme levels have been shown to be relatively high in mouse and/or human stomach, bladder, intestine, colon and kidney, but are usually low in liver, lung and haematopoietic cells (Benson et al, 1980;Schlager and Powis, 1990;Smitskamp-Wilms et al, 1995). DT-diaphorase activity is higher in some tumour cells than in the corresponding normal cells, with elevated levels of enzyme activity having been observed in human liver, colon, breast and lung tumour cells (Schlager and Powis, 1990;Malkinson et al, 1992;Belinsky and Jaiswal, 1993;Smitskamp-Wilms et al, 1995).…”

To determine the cytotoxicity of chlorambucil and one of its nitro-derivatives, conjugated to prasterone and pregnenolone, towards eight human cancer cell-lines

“…hydroquinones and nitroso compounds, respectively [32]. In addition, there is an over expression of DT-diaphorase throughout many tumor tissues [33,34] and its activity and gene expression have been found to be up regulated in comparison to tissue levels in lung, colon, liver and breast tumors [35,36]. DT-diaphorase is therefore an attractive target for the development of bioreductively activated chemotherapeutic agents [37].…”

Reduction of mitomycin C is catalysed by human recombinant NRH:quinone oxidoreductase 2 using reduced nicotinamide adenine dinucleotide as an electron donating co-factor

“…As a prodrug, the parent compound is relatively nontoxic compared to the highly electrophilic metabolites formed following sequential or simultaneous two electron reduction of the quinone to the hydroquinone (Iyer and Szybalski, 1963). Many enzymes have been implicated in the catalysis of MMC including NQO1 (Siegel et al, 1992) and interest in NQO1-directed cancer chemotherapy arose following the observation that NQO1 is more highly expressed in tumour tissue when compared with matched healthy tissue, for example lung (Schlager and Powis, 1990).…”