Dose effects in gene environment interaction: an enzyme kinetics based approach.
There have been many observations of different forms of the effect of dose in toxicological and pharmacological research into gene environment interactions. In one form, the effect of genetic variation is seen to be more potent at lower doses, while in the other, the genetic variant has a stronger effect at higher doses of exposure. The application of principles of classical enzyme kinetics to this problem has led to a hypothesis that for any gain of function polymorphism, a low exposure gene (LEG) or low dose effect will always be observed, while for any loss of function polymorphism, the high exposure gene (HEG) effect will always be seen. Furthermore the dose effect is found to be independent of any effects on Vmax, but is related to effects on Km of the gene product. The hypothesis is derived from the Michaelis-Menten equation, and if supported by experimental evidence, could lead to important implications for drug dosage and toxicological risk analysis in the context of individual differences in genetic profiles.
Garte
Seymour
S
Molecular Carcinogenesis Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5150 Center Av Suite 1A, Pittsburgh, PA 15232, USA. gartesj@upmc.edu