Regulatory polymorphisms and their contribution to interindividual differences in the expression of enzymes influencing drug and toxicant disposition.
The unexpected paucity of human protein encoding genes suggested that polymorphisms altering gene expression might be more important than initially thought. From an evolutionary perspective, traits such as xenobiotic metabolism and transport that require a dynamic response to environmental changes would evolve more efficiently through variation in regulatory sequences versus coding variants. Such variation would be manifest as co-dominant traits and selection pressures would operate more efficiently because of their ability to impact fitness in the heterozygous state. Our current understanding of regulatory polymorphisms impacting drug disposition is reviewed including specific discussion regarding knowledge gaps and future research opportunities.
Hines
Ronald N
RN
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. rhines@mcw.edu
Koukouritaki
Sevasti B
SB
Poch
Mark T
MT
Stephens
Michael C
MC
D001711:Biotransformation / Q000235:genetics; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010641:Phenotype; D011110:Polymorphism, Genetic; D014166:Transferases / Q000235:genetics
D004798:Enzymes; D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations; D010088:Oxidoreductases; D014166:Transferases; D004851:Epoxide Hydrolases