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Pharmacogenetics in biological perspective

W Kalow1

  • 1Department of Pharmacology, University of Toronto, Ontario, Canada.

Pharmacological Reviews
|January 27, 1998
PubMed
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Pharmacogenetics, the study of how genes affect drug response, is found across all life. This heritable variation, crucial for population survival through Darwinian selection, impacts drug targets, metabolism, and transport.

Area of Science:

  • Pharmacogenetics and evolutionary biology
  • Population genetics and xenobiotic interactions

Background:

  • Pharmacogenetics, heritable variation in response to xenobiotics, is a fundamental characteristic of populations across all life forms.
  • Individual variations in drug response can confer survival advantages through Darwinian selection, highlighting the role of genetic diversity in population resilience.
  • Such variations influence drug targets, metabolism, and transport, with metabolic variations appearing most prominent, though their evolutionary drivers remain unclear.

Purpose of the Study:

  • To explore the concept of pharmacogenetics as a population-level phenomenon.
  • To compare pharmacogenetic resistance mechanisms with host resistance to pathogens.
  • To understand the preadaptive nature and evolutionary maintenance of pharmacogenetic diversity within populations.

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Main Methods:

  • Comparative analysis of pharmacogenetic variation across different species (insects, bacteria, humans).
  • Examination of genetic host resistance in mammals against various diseases (malaria, tuberculosis, etc.).
  • Review of existing literature on pharmacogenetic variants, their frequencies, and evolutionary implications.

Main Results:

  • Pharmacogenetic variation is a universal trait, essential for population survival via Darwinian selection.
  • Metabolic variations are a significant component of pharmacogenetic diversity, though their evolutionary significance requires further investigation.
  • Genetic host resistances in mammals share similarities with pharmacogenetic variations, offering insights into long-term evolutionary adaptations.

Conclusions:

  • Pharmacogenetic diversity is largely preadaptive, with variants maintained through heterozygote advantage or selective neutrality, minimizing biological costs to the population.
  • Inter-population differences in gene frequencies and nucleotide substitutions underscore the typicality of pharmacogenetic divergence.
  • Future pharmacogenetics research must integrate both random and monogenic variations to fully understand drug response diversity.