Genetic and environmental factors affecting the metabolism of carcinogens

The metabolism of some drugs and carcinogens in man is highly complex, involving many different enzymes. In addition, multiple factors (Table 1) can alter rates of metabolism, as well as rates of absorption, distribution and excretion of certain drugs and carcinogens, thereby affecting critical reaction site concentrations of these drugs as well as of proximate and ultimate carcinogens. Since ethical restrictions prohibit investigation of carcinogens in humans in vivo, we employed instead safe test compounds, such as antipyrine and tracer doses of 14C-aminopyrine as models of carcinogens; changes in their disposition could be quantitated and attributed to the imposition of some of the factors and conditions listed in Table 1. In addition to genetic factors that control large interindividual variations in drug and carcinogen disposition among normal human subjects under basal conditions, many environmental factors were identified as being capable of altering rates of drug or carcinogen elimination. In patients, a complex, dynamic interaction occurs certain environmental factors listed in Table 1 and underlying genetic factors that under basal conditions control large interindividual variations in drug disposition. From the point of view of constructing and interpreting tests for detection of carcinogens, these results suggest the existence of extreme differences among human subjects in rates of carcinogen absorption, distribution, metabolism and excretion due to the episodic presence and action of multiple genetic and environmental factors capable of affecting each of these processes. Therefore, the hazard must be recognized and avoided of extrapolating results derived from only a few subjects under a particular set of conditions to many other subjects with different genetic constitutions and environmental backgrounds.