Perspectives in Pharmacology Genetics and Susceptibility to Toxic Chemicals: Do You (or Should You) Know Your Genetic Profile?

This review is based on a symposium/roundtable session, sponsored by the Division of Toxicology of the American Society for Pharmacology and Experimental Therapeutics, that was held at the 2002 Experimental Biology meeting in New Orleans, LA. The focus is on the role of pharmacogenomics in determining individual susceptibility to chemically induced toxicity. An individual’s risk of disease from exposure to toxic chemicals is determined by a complex interplay between genetics, physiology, and concurrent or prior exposures to drugs and other chemicals. The first section of the review defines the basics of pharmacogenetics and pharmacogenomics and assesses the current state of the science. Selected applications to specific enzyme systems are summarized by way of example. New, state-of-the-art approaches to studying genetic determinants of susceptibility, including analytical methods and transgenic technology, are then discussed. Finally, ethical and legal concerns with the application of this knowledge and methodology to human health will be discussed. Pharmacogenetics and Susceptibility to Toxic Chemicals: Historical Perspective, Current Status and Future Challenges The objective of this article is to place the field of pharmacogenetics and pharmacogenomics into historical perspective, to review its current status, and also to examine the promises and challenges of the future. But what is pharmacogenetics and what is the difference between this term and pharmacogenomics—a phrase that has arisen much more recently? In fact, both involve the study of genetically determined variation in xenobiotic response. Pharmacogenetics has classically focused on one or perhaps two loci to explain intersubject variation, however. With improvements in analytical technology coupled with the sequencing of the human genome and the technological advances spurred by this endeavor, as well as improvements in data analysis, it has become possible to take a more global approach to underlying causes of variation, thus the advent of the field of pharma-