Population studies of polymorphism in drug oxidation and its relevance to carcinogenesis

Metabolic oxidation plays a central role in both the detoxication and chemical activation of many environmental procarcinogens. A plethora of in vitro data suggests that metabolic activation and subsequent DNA covalent binding of such substances vary widely between individuals. The need for a simple test in vivo of human variability in metabolic oxidation is apparent, not only to help understand the variation in disposition of many drugs and other chemicals, but also as an aid to predicting individual cancer risk from metabolically activated procarcinogens. Current methodology has failed to provide such information for a number of reasons, which are discussed. A genetic polymorphism affecting the metabolic disposition and biological effects of a number of drugs is described. Persons can be phenotyped as either extensive or poor metabolizers, using the drug debrisoquine. The measured variable, urinary 'metabolic ratio', which is distributed across these two phenotypes with values of 0.1 to 200, gives a clear indication of the metabolic behaviour of many drugs and, possibly therefore, of certain procarcinogens. Accordingly, two groups of cancer patients were investigated with debrisoquine, namely Nigerians with hepatocellular and related tumours and white smokers with bronchial carcinoma in the United Kingdom. These preliminary studies are suggestive of a phenotype component in relative cancer risk, poor metabolizers appearing to be less vulnerable. Animal model data seem to confirm a relationship between aflatoxin B1 metabolism and DNA binding and polymorphic debrisoquine oxidation. It is concluded that the biological consequences of ingesting exogenous chemicals may be better understood from studies of discrete, genetically determined steps in their interaction with living systems.