The distribution of debrisoquine metabolic phenotypes and implications for the suggested association with lung cancer risk

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Abstract
Debrisoquine hydroxylation exhibits wide inter-individual variation in Caucasian populations. After similar doses of the drug, extensive metabolizers excrete up to several hundred times more of the urinary metabolite 4-hydroxy-debrisoquine than do poor metabolizers. The phenotypes have traditionally been defined by the metabolic ratio (MR), or the molar ratio of debrisoquine to its chief metabolite recovered in an aliquot of an eight hour urine sample, after a test dose of the drug. Deficient metabolism is inherited as an autosomal recessive condition. We have reanalyzed previously published data from a study of lung cancer patients and controls using a computerized optimization method to more accurately estimate the parameters describing the three phenotypic distributions. Using these new distributions to categorize controls, we show that Hardy-Weinberg conditions are now fulfilled. When the newly defined phenotype parameters are employed to assign the phenotypes of cases and controls, a highly significantly difference in phenotype distribution between cases and controls is still observed. This result supports the hypothesis that the debrisoquine metabolic phenotype may be associated with lung cancer susceptibility.