Genetic and environmental factors causing variation in drug response

Area of Science:

• Pharmacogenetics
• Toxicology
• Metabolomics

Background:

• Significant interindividual pharmacokinetic variations (4- to 40-fold) exist within populations.
• These variations influence cancer risk by altering the metabolic activation of environmental carcinogens.
• Hepatic cytochrome P-450 (CYP450) isozymes are crucial for xenobiotic metabolism and activation.

Purpose of the Study:

• To identify genetic and environmental factors contributing to large interindividual variations in xenobiotic metabolism.
• To understand the role of CYP450 isozymes in differential susceptibility to carcinogens.
• To evaluate the utility of marker drugs in assessing pharmacokinetic capacity.

Main Methods:

• Utilized twin and family studies to investigate pharmacogenetic hypotheses.
• Employed marker drugs to assess pharmacokinetic capacity in individuals.
• Stressed stringent environmental control in subject selection for genetic studies.

Main Results:

• Demonstrated monogenic control over variations in the activity of approximately 12 CYP450 isozymes.
• Highlighted dynamic interactions between genetic and environmental factors influencing metabolism.
• Showcased the sensitivity of CYP450 isozymes to environmental perturbations.

Conclusions:

• Genetic factors significantly contribute to interindividual differences in xenobiotic metabolism and associated health risks.
• Careful control of environmental factors is essential for accurate genetic studies in pharmacogenetics.
• Understanding individual metabolic pathways is critical, especially for drugs metabolized by multiple pathways.