Debrisoquine metabolism and genetic predisposition to lung cancer

Abstract

It is usually the metabolites of environmental carcinogens that initiate a cancer (Miller & Miller, 1983), and if the metabolism were subject to genetically determined polymorphism, there could be variation between smokers in their susceptibility to smoking-related lung cancer. We report a case-control study using the drug debrisoquine as a potential marker of such genetically determined susceptibility to lung cancer.Debrisoquine has only one major metabolite, 4-hydroxy debrisoquine (Idle et al., 1979), and the extent of 4-hydroxylation before excretion is controlled by a single gene and segregates into two distinct phenotypes -autosomal recessive poor metabolisers (about 9% of white populations, hydroxylating only 1-2% of a 10mg dose of debrisoquine) and homozygous and heterozygous dominant extensive metabolisers (hydroxylating 10-99%) (Evans et al., 1980;Steiner et al., 1985). Unchanged and 4-hydroxy debrisoquine can be measured easily and with high reproducibility (r=0.88) in urine (Evans et al., 1980 We recruited consecutive caucasian inpatients with newly diagnosed lung cancer from a London hospital. Cigarette smoking histories were documented as accurately as possible and recorded in pack-years (one-twentieth the average daily number of cigarettes smoked multiplied by the number of years of smoking). Subjects whose total cigarette consumption was less than 10 pack years, or who had given up smoking more than five years previously were excluded. We also excluded patients with elevated serum bilirubin (>25mmoll-1), and those who were taking drugs known to induce oxidising enzymes (e.g. barbiturates) or to compete with debrisoquine for oxidation (Sloan et al., 1978;Eichelbaum, 1984). A total of 104 cases were included. The histological types were squamous cell (38 cases), large cell (22), small cell (31), adenocarcinoma (11) and undifferentiated (2), diagnosed histologically (92) or cytologically (12). The 104 control subjects were residents of three homes for ex-servicemen (70), inpatients with various non-malignant diseases (22) Cases and controls took a single 10mg debrisoquine tablet at 7 a.m. and made an 8 h urine collection, from which aliquots were stored at -20°C to await analysis by electroncapture gas-chromatography (Idle et al., 1979). The ratio of unchanged to 4-hydroxy debrisoquine concentration, the metabolic ratio, was used to assign phenotype, the antimode

The debrisoquine metabolic phenotype and DNA-based assays: implications of misclassification for the association of lung cancer and the debrisoquine metabolic phenotype.

“…The metabolism of the anti-hypertensive drug debrisoquine (DBR) is under autosomal genetic control (1)(2)(3), and inheritance of the trait conferring ability to "extensively" metabolize the drug has been suggested as a host susceptibility factor for lung cancer. Studies consistent with a genetic component to lung cancer susceptibility (4)(5)(6)(7) and studies to test the hypothesis of an association between DBR metabolism and lung cancer (8)(9)(10)(11)(12)(13)(14) are reported.…”

The rationale for case‐control methodology in epidemiological studies of cancer risk (response to Speirs et al., 1990) [see comments]

“…These include Ayesh et al (1984), Caporaso et al (1988), Law et al (1989) and Roots et al (1988). The frequency of poor metabolisers (PM) reported in these studies is in the aggregate significantly lower than that in the general population but more importantly, each of these studies included a well-defined control group thereby allowing an appropriate case-control comparison.…”

Genetic Polymorphism of Sparteine/Debrisoquine Oxidation: A Reappraisal

“…Accordingly, possible relationships between polymorphic drug metabolism and susceptibility to disease have aroused much interest. The SP/DB phenotype has been investigated in relation to several disorders and significant associations have been observed with lung (Ayesh et al 1984;Law et al 1989) and bladder cancer (Kaisary et al 1987), Parkinson's disease (Barbeau et al 1985) and systemic lupus erythematosus (Baer et al 1986). The data regarding cancer of the lung are conflicting.…”