At our seminar yesterday, Mark Thomas put us onto work by Daniel Nebert. A long-time leaders in pharmacogenomics, he has written several papers offering an evolutionary framework for thinking about genes that influence drug metabolism. Suddenly, all kinds of things make sense. Why 57 genes in the Cytochrome P450 super-gene family? Because they are products of co-evolution between plants trying to defend themselves and herbivores looking for a meal. All the genes can be traced back to a common ancestor about 2 billion years ago, but the fast differentiation, espcecially in the CYP2 family, came about 400 million years ago as animals moved onto land to be come a problem for plants.
The implications are profound:
The entire ﬁeld of pharmacology and drug development represents the discovery and characterization of naturally occurring plant metabolites, followed by synthesis of analogs that are found to do a better job with fewer side effects (2006, p4)
His perspective gets us away from thinking about drug metabolizing enzymes-they evolved to deal with endogenous and exogenous substances long before there were drugs, and they are active not only in liver, but in every cell in the body. He also notes that we should not ony expect to find major differences between species depending on their diet, we should expect to find that these systems are inducable by exposure, as of course, they are.
The discussion inspired a new idea. Our ancestors routinely ate somewhat toxic plants until just the past 5-10,000 years. Agriculture and plant breeding now allow us to eat mild tasting foods. I wonder if the resulting inadequate stimulation of "drug" metabolising enzymes may be responsible for some diseases of civilization. This should certainly be testable in rats. Probably it has already be done. If you know about such studies, please leave a comment below.
Nebert DW, Dieter MZ (2000) The evolution of drug metabolism. Pharmacology 61: 124-135
Nebert DW (2006) Drug metabolism: Evolution. Encyclopedia of Life Sciences: Wiley Press (online). pp. 1-6.