ROLE OF CYTOCHROMES P450 IN DRUG-METABOLISM AND HEPATOTOXICITY

The cytochromes P450 may represent the major metabolic frontier between the environment and the body. The recent discovery of interpatient differences in P450 profile has provided a plausible explantation for heterogeneous dosing requirements for some individual drugs. The heterogeneity in P450 profiles appears to also account for some ''idiosyncratic'' drug reactions, especially hepatotoxicity. An important challenge for the future is the development of safe and noninvasive tests capable of determining patients' P450 profiles. It is likely that such tests will greatly facilitate individualization of dosing of many drugs in the future. In addition, such tests should be useful in identifying patients likely to develop ''idiosyncratic'' toxicity to specific drugs. Finally, it seems likely that interpatient differences in P450 profile may at least in part explain interpatient differences in susceptibility to environmental diseases. For example, it may in the future be possible to identify individuals with P450 profiels that render them susceptible to leukemia from xenobiotics such as benzene. Such individuals could be advised not to work in an environment containing these chemicals or, alternatively, to take a medication which reduces their risk by appropriately altering their P450 profile. Identification and in vitro characterization of human P450s is now well underway and may be largely completed within the next decade. However, studies addressing the clinical significance of interpatient differences in P450 profile, as well as the genetic and nongenetic factors that underlie this heterogeneity, are just beginning. This should remain a rewarding area of research for many years to come.