Polymorphisms in the NAD(P)H: quinone oxidoreductase gene and small cell lung cancer risk in a UK population
Introduction
NAD(P)H: quinone oxidoreductase (NQO1) catalyses the 2-electron reduction of quinones to hydroquinones [1]. In doing so, NQO1 protects the cell against cytotoxicity by reducing the concentration of free quinone available for single electron reduction. This pathway is thought to be the major mechanism responsible for the toxicity of quinones, including those arising from benzo(a)pyrene, one of the most potent polycyclic aromatic hydrocarbons present in tobacco smoke [2]. NQO1 may also, however, play a role in the reductive activation of antitumor quinones, such as mitomycin C and environmental carcinogens, such as the heterocyclic amines [3].
NQO1 protein has been detected in normal lung respiratory epithelium, suggesting that NQO1 plays a role in protecting the lung against damage [4]. NQO1 activity can be induced by different dietary chemicals including flavonoids and cigarette smoking has been associated with levels of this enzyme in the lung [5], [6]. In a small number of tumour samples, NQO1 was overexpressed in nine non-small cell lung cancers, but no expression of this enzyme was found in three small cell tumours [4] , potentially as a result of a lack of those trans-activating factors of the AP-1 family which mediate NQO1 expression [7]. An alternative explanation for the loss of expression is that small cell lung patients have a mutant NQO protein, which results from a point mutation (C to T) at position 609 in the NQO1 gene and which exhibits just 2% of the enzymatic activity of the wild-type protein [8]. If this lack of expression in small cell tumours is replicated in a larger study, then it may suggest that lack of NQO1 expression results from the carcinogenic process or is involved in the aetiology of the tumour.
The wildtype NQO1 genotype has been associated with an increase in lung cancer risk in African- and Mexican-Americans, Japanese and Taiwanese populations [9], [10], [11], consistent with a role of the protein in activating environmental carcinogens. In contrast, the frequency of the mutant NQO1 genotype was reported to be higher in lung cancer cases when compared to a reference panel, but not a local healthy population [12], providing some evidence that the enzyme may confer protection against cigarette smoke. As 4% of the British population lack appreciable NQO1 tissue activity [13], we have studied the risk associated with the NQO1 genotype in a Caucasian population attending a bronchoscopy unit for diagnosis of malignant and non-malignant lung disease.
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Study population
Between March 1996 and April 1997, 395 patients attending 109 bronchoscopy clinics at the North West Lung Centre (Manchester, UK) were asked to take part in the study. Subjects included everyone over the age of 18 who were well enough to take part. Of these patients, 90.8% of lung cancer patients (118/130) and 91.7% of all other patients (243/265) agreed to be entered into the study. All subjects were interviewed using a structured questionnaire to obtain information on patients’ ethnicity,
Results
There were no significant differences in gender, number of cigarettes smoked per day and the age smoking began between the cases and controls (Table 1). However, cases were significantly older than controls (P=0.001), were more likely to have been ever-smokers (OR=16.2, 95% C.I.=4.01–140.7) and smoked for longer (P<0.001).
NQO1 genotypes were determined in 227 patients. The frequency of NQO1 wt/wt, wt/mut, mut/mut genotypes was 68.3, 29.3 and 2.4%, respectively in all cases and 76.6, 22.1 and
Discussion
The NAD(P)H: quinone oxidoreductase enzyme is known to play a major role in the detoxification of xenobiotics, including benzo(a)pyrene [15] and there is evidence to suggest that this enzyme is induced in the lung in response to cigarette smoke [5]. NQO1 has been detected at high levels in normal respiratory epithelium and in tissue from adenocarcinoma and squamous cell carcinoma tumours. However, this enzyme has not been detected in small cell lung tumours [3], suggesting that the lack of NQO1
Acknowledgements
The authors wish to thank the staff at the Bronchoscopy Unit of the North West Lung Centre, Wythenshawe Hospital. This work was funded by a bequest fellowship for SJL from the University of Manchester and in part by the Cancer Research Campaign.
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